- Email: [email protected]
Antibiotic innovation for future public health needs
Accepted Manuscript Antibiotic innovation for future public health needs Ursula Theuretzbacher PII:
S1198-743X(17)30344-0
DOI:
10.1016/j.cmi.2017.06.020
Reference:
CMI 988
To appear in:
Clinical Microbiology and Infection
Received Date: 29 March 2017 Revised Date:
17 June 2017
Accepted Date: 19 June 2017
Please cite this article as: Theuretzbacher U, Antibiotic innovation for future public health needs, Clinical Microbiology and Infection (2017), doi: 10.1016/j.cmi.2017.06.020. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Antibiotic innovation for future public health needs
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Ursula Theuretzbacher
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Theme Issue
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Eckpergasse 13, 1180 Vienna, Austria
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[email protected]
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+436503801518
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Running title: Antibiotic innovation
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Center for Anti-Infective Agents
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Key words: antibiotic, discovery, innovation, cross-resistance, resistance
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Abstract
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Background: The public health threat of antibiotic resistance has gained attention at the highest
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political levels globally, and recommendations on how to respond are being considered for
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implementation. Among the recommended responses being explored for their feasibility is the
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introduction of economic incentives to promote research and development (R&D) of new antibiotics.
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There is broad agreement that public investment should stimulate innovation and be linked to
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policies promoting sustainable and equitable access to antibiotics. Though commonly used, the term
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‘innovation’ is not based on a common understanding.
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Aims: This article aims to initiate discussion on the meaning of ‘innovation’ in this context.
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Sources: Literature and expert opinion
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Content: As the definition of a novel class (novel scaffold, novel pharmacophore), a novel target
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(novel binding site) and a novel mode of action – the three traditional criteria for ‘innovation’ in this
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context – may be confounded by the complexities of antibacterial drug discovery, a biological and
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outcome-oriented definition of innovation is presented to initiate discussion. Such an expanded
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definition of innovation in this specific context is based on the overarching requirement that a drug
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not be affected by cross-resistance to existing drugs in the organisms and indications for which it is
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intended to be used, and that it have low potential for high-frequency, high-level single-step
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resistance if intended as a single drug therapy.
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Implications: Policy makers, public health authorities and funders could use such a comprehensive
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definition of innovation in order to prioritise where publicly funded incentives should be applied.
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Introduction
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Recent national and international high-level policy initiatives highlight the growing awareness of the
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increasing bacterial resistance to current antibiotics. This public health threat is receiving significant
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political attention. Multiple concerted actions concerning human and animal health, as well as
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ACCEPTED MANUSCRIPT pharmaceutical production and environmental sector policies, are recommended and need to be
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implemented. Considered urgent are: robust surveillance globally, responsible and optimized use of
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existing antibiotics, better infection control, increased research activities in the antibacterial field,
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restricting antibiotic use in animals, limiting antibiotic pollution of the environment, and economic
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incentives to stimulate and incentivize research, discovery and development of new antibacterial
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drugs to fill the neglected pipelines [1]. Such incentives will require substantial public investment.
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There is broad agreement that public investment should stimulate innovation and be linked to
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policies that promote sustainable and equitable access to antibiotics. The critically needed
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innovation in antibacterial drug discovery is expected to counteract the increasing trend of multidrug
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resistant (MDR), extensively drug resistant (XDR) and even pan-drug resistant (PDR) pathogens,
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especially Gram-negative bacteria as outlined in the recently published WHO priority pathogen list
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for R&D [2]. The often-used term ‘innovation’ has been used in a broad and indiscriminate way and
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has lost specific meaning. If policy initiatives are implemented, the requirement for innovativeness as
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a prioritisation tool needs to be discussed and defined. Europe’s Innovative Medicines Initiative (IMI)
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has financed a project, DRIVE-AB (i.e., Driving reinvestment in research and development for
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antibiotics and advocating their responsible use, www.drive-ab.eu), to provide scientific evidence for
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new reward models and to test the feasibility of their implementation [3]. If stimulating innovation in
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antibacterial drug discovery and development is to be a major factor of economic incentives, there is
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a need to reach a workable definition of ‘innovation’ and this is vital for matching public investment
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with future public health needs. As priority-setting requires a broad discussion and consensus
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considering the complexities of discovery, this article aims to initiate discussion on the meaning of
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‘innovation’ in this context. The discussion is focused on conventional, directly acting, antibacterial
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drugs that have not been used in human or veterinary medicine before worldwide. Other
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approaches, such as preventive strategies, immunomodulatory, adjunctive therapies that target
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virulence or resistance gene regulators, monoclonal antibodies, topical drugs and antibiotics against
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Mycobacterium tuberculosis, are not covered in this article.
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Current clinical antibiotic pipelines and short-term perspective
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Nearly all antibiotic classes we are using today were discovered during the Golden Age of antibiotic
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innovation, which extended from the 1940s to the 1960s [4]. Numerous modifications to the initial
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discoveries improved their utility and extended the life of these antibiotic classes. Efforts to modify
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the chemical structures were focused on circumventing emerging class-specific target-based or drug-
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modifying resistance mechanisms or on lower affinity for efflux pumps as well as improving
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pharmacokinetics and extending the activity spectrum. The beta-lactam class exemplifies best the
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success of this strategy. Methicillin and the isoxazolylpenicillins (Staphylococcal penicillins) were
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introduced following the rising frequency in resistance to penicillin due to the production of
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penicillinases. Third generation cephalosporins were introduced to solve the problem of beta-
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lactamases like TEM, ceftriaxone enabled a once-a-day dosing due to its extended half-life, and
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ceftazidime and ceftolozane included Pseudomonas aeruginosa in their Gram-negative spectrum.
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Despite these successes, the ever-increasing range of beta-lactamases required an alternative
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approach. The concept of a protector drug was born - the combination of vulnerable beta-lactams
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with a beta-lactamase inhibitor. After a great success of the combinations amoxicillin/clavulanic acid
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and piperacillin/tazobactam this concept has been revived and is still one direction of R&D efforts
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(Figure).
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The last years have seen a resurgence of discovery & development activities, mostly in small
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companies, often with the concept of modifying compounds in existing classes using cutting-edge
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methods to fix specific class-related resistance problems [5]. Basing a drug discovery project on a
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well validated lead carries less risk than starting from scratch. Most antibiotics in clinical
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development are modifications of classes that have been extensively used in human or animal health
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(Figure). The downside of modifying known chemical structures is that, usually, multiple mechanisms
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of resistance exist for every class of antibiotics and not all relevant resistance mechanisms can be
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addressed by chemical modification. Some cross-resistance to existing antibiotics usually remains.
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Thus, due to the selection of less common resistance mechanisms or the appearance of previously
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ACCEPTED MANUSCRIPT unknown ones [6,7] modifications within existing antibiotic classes may only buy some time [8]. In
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the long run, innovation is needed to find novel drugs without pre-existing cross-resistance that can
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be further improved in future efforts.
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How to define innovation?
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Although there is general agreement that we need ’innovation’ in antibiotic R&D to respond now to
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anticipated future medical needs, the lack of clarity around ’innovation’ itself presents a challenge.
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The word innovation is one of the most commonly used terms in national and international initiatives
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that address the antibiotic resistance problem, but what is meant by ‘innovation’ or how different
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stakeholders interpret the term is unclear. In the context of stimulating the discovery of novel
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antibiotics that can address the most resistant pathogens and meet anticipated future public health
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needs, policy makers and public health authorities need a workable definition of innovation in order
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to prioritise incentives to be underwritten with public funds.
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Discovery programmes may take 15 years or longer [9]. Therefore, when defining innovation in this
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context, it is essential to consider longer-term resistance trends, scientific challenges, and the most
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urgent anticipated public health needs. Innovation is commonly associated with a novel antibiotic
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class, a novel target (binding site) or a novel mode of action. However, these terms are not clearly
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defined and are open to broad interpretation. Some aspects of these terms are discussed below
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before suggesting additional criteria.
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Novel antibiotic class
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Antibiotics are historically grouped into antibacterial classes. The classes are defined according to the
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active chemical scaffold (e.g. ß-lactams, fluoroquinolones) or functional aspects (e.g. topoisomerase
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inhibitors, beta-lactamase inhibitors). Chemical classes are groupings that relate compounds by
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similar features, usually by their active chemical structure (pharmacophore). Assignment of a new 5
ACCEPTED MANUSCRIPT compound to an antibacterial class or subclass is sometimes influenced by marketing considerations
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and the desire to differentiate a drug from existing ones. Creating new classes or subclasses may be
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an appealing way to influence user perception. An example is the glycyl derivative of minocycline,
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tigecycline, which is a member of the tetracycline chemical class but was described as the first
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member of a new class called glycylcyclines [10]. Another example is the ketolide class, which was
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created many years ago for telithromycin because it contains a keto function [11]. The ketolide
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classification fell out of favour after evidence of the toxicity of telithromycin emerged, and later
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derivatives were preferably associated with the macrolide class to prevent the association with
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toxicity. Classifying new drugs may be a longer process until agreement is achieved as no rules exist
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and terminology may change. Fluoroquinolones are grouped according to their chemical core
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structure and their ability to inhibit the essential bacterial enzymes DNA gyrase and topoisomerase
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IV. A new group of antibiotics with a different chemical scaffold also inhibits DNA gyrase and
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topoisomerase IV with a different mode of action [12]. They are called Novel Bacterial type II
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Topisomerase Inhibitors, thus grouped according to their function. This is a recent example of the
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creation of a new class of antibiotics based on functional and not chemical aspects. These examples
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show that there is no clear and broadly accepted definition of what constitutes a novel antibacterial
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class. A more precise term would be a new active chemical structure, scaffold or pharmacophore. To
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complicate things further, the concept of a novel antibacterial class as a major pillar of innovation
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may not be sufficient for future XDR and PDR pathogens. Even novel chemical scaffolds that are not
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used in existing antibiotics may show cross-resistance (also called co-resistance) with unrelated
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structures in cases where they share overlapping binding sites on the same bacterial target or are
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affected by unspecific resistance mechanisms such as efflux.
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Novel bacterial target
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When it comes to meeting the test of innovation through a novel bacterial target, criteria for a ‘new
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target’ may be too vague, as the term ‘target’ is not defined and may be complicated by the
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existence of more than one specific binding site. Besides the definition of a binding site a target is
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ACCEPTED MANUSCRIPT often perceived to be a functional structure, such as the ribosome or the cell wall. The ribosome
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target has been exploited extensively over the history of antibiotics, as it has multiple binding sites
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which are used by many antibiotics of different chemical scaffolds. The recent advances that X-ray
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crystallography has brought to the understanding of the structure and function of the ribosome has
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revealed the molecular details of the various antibiotic-binding sites [13]. Some of these binding sites
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are in close proximity and may be overlapping. If a resistance mechanism affects a specific binding
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site, all different chemical scaffolds that share this binding site may be affected. Well-known
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examples are MLSB-resistance affecting macrolides, lincosamides, and streptogramin B or PhLOPSA-
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resistance based on the cfr gene (RNA methyltransferase) and affecting phenicols, lincosamides,
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oxazolidinones, pleuromutilins, and streptogramin A.
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Specific cases that highlight the difficulties to classify a drug as novel include antibiotics with targets
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that have not been used in human medicine for systemic infections but in other fields. This includes
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lefamulin, a drug in phase 3 clinical development. It belongs to the class of pleuromutilins that have a
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long record in the field of animal farming (tiamulin/valnemulin) but also topical human use for
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superficial skin infections (retapamulin). Though targeting different pathogens in veterinary medicine
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the impact of possible exchange of resistance determinants between bacterial species and longer-
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term influence of prior and current use on the development of resistance in human health is not
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known [14]. Transferable resistance to pleuromutilins due to vga genes has emerged globally in
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livestock-associated MRSA [15]. Another example is the functional class of FabI inhibitors, with one
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drug in active clinical development for the treatment of staphylococcal infections, as well as the non-
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specific biocide and slow-binding FabI inhibitor triclosan. Due to its dual mode of action triclosan has
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been widely used as a disinfectant in consumer products and point mutations in the FabI target site
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of staphylococci are well described [15,16]. Selection pressure due to triclosan use may have been
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exerted before the introduction of the new FabI inhibitors in clinical trials for the systemic treatment
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of staphylococcal infections.
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ACCEPTED MANUSCRIPT Novel mode of action
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The ‘mode of action’ is often complex not always understood at early phases of discovery and
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development and the term is rather vague. It has been used in a general functional way, for instance
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to identify topoisomerase inhibitors by the fact that they inhibit DNA replication. Molecular details of
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how these drugs interact with their target have only recently been described [17]. For many
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antibiotics, especially the natural products, the mode of action may be complex and may not be
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entirely revealed until they are widely used. Different affinities for primary and secondary binding
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sites may influence the terminology. Additionally, different chemical solutions may bring about
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analogous features of mechanisms of action as has been shown for some cationic antimicrobial
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peptides and anionic lipopetides such as daptomycin [18,19]. The mode of action describes the sum
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of all effects that an antibacterial agent exerts in/at a cell. Such complex and pleiotropic effects may
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not be deciphered early on. Therefore, basing the concept of innovation solely on “mode of action”
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may not be sufficient and should be expanded to additional criteria.
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A biological approach
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As shown in the sections above, what is meant by a novel class, novel target or novel mode of action
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is not clear, especially in the context of resistance. All that matters for treating patients with MDR,
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XDR or PDR pathogens is having antibiotics available to which these highly resistant pathogens are
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reliably susceptible. As the currently used terminology is diffuse adding a biological definition of
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innovation may be more meaningful. A biological definition of innovation in the above-described
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context is based on the requirement that a drug not be affected by cross-resistance to existing drugs
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in the organisms for which it is intended to be used, and that it have low potential for high-
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frequency, high-level single-step resistance. This definition of innovation would satisfy the need for
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prioritising novel antibiotics against the most resistant pathogens that are expected to burden
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patients and health care systems even more in the future.
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Cross-resistance occurs when resistance to a specific drug influences susceptibility and resistance to
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other antibiotics simultaneously [20]. This is a well-known phenomenon for antibiotics within the
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same class; for example, the acquisition of extended spectrum beta-lactamases (ESBL) caused cross-
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resistance within the class of penicillins, cephalosporins and monobactams. Recent modifications of
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known antibiotic classes commonly address such class-specific resistance mechanisms. Plazomicin, a
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derivative of the aminoglycoside sisomicin was designed to resist modification by most
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aminoglycoside-modifying enzymes [21]. Although this is the most common resistance mechanism,
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target resistance due to modification mediated by ribosomal methyltranferases may equate to cross-
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resistance to other aminoglycosides. The epidemiology of specific resistance mechanisms determines
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the clinical relevance of the cross-resistance. For example, eravacycline, a new synthetic tetracycline,
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shows an overlapping MIC distribution with tigecycline among the enterobacteriaceae and
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Acinetobacter baumanii. Though demonstrating mostly 2-4 fold lower MICs, eravacycline MICs reflect
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the rise of tigecycline MICs above the susceptibility breakpoint, thus, leading to close correlation
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between MICs of both molecules and demonstrating a significant level of cross-resistance with
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tigecycline [22].
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Cross-resistance may extend beyond class-specific resistance. Non-specific resistance mechanisms
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can confer resistance (also called co-resistance) to antibiotics of different classes [23]. Well-known
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examples are mutations that alter the expression of efflux pumps or cell wall porins [24] and affect
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several unrelated antibiotics. It has been recently shown that reduced eravacycline and tigecycline
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susceptibility in a subset of carbapenem-resistant KPC-producing Klebsiella pneumoniae isolates is
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most likely due to upregulated efflux pumps [22,25]. A newly approved antibacterial product,
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ceftazidime/avibactam, was developed to escape the degradation by more beta-lactamases than
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existing beta-lactamase inhibitor combinations. Although the spectrum of beta-lactamases that are
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inhibited by avibactam is extended, some of the most resistant pathogens, such as MDR
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Pseudomonas aeruginosa [26], may still survive by a combination of the effects of increased drug
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ACCEPTED MANUSCRIPT efflux and decreased cell permeability. Testing a new drug candidate early on against a panel of XDR
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clinical as well as genetically defined strains would be most important [27].
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Low potential for rapid resistance evolution
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Innovative novel drugs that inhibit a single molecular target or a target that can be bypassed easily
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have a high potential for rapid resistance evolution [13, 28-30]. A single mutation in the target-
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determining gene can lead to single-step high-level resistance with potentially rapid emergence of
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resistance during therapy. Examples of old single-target drugs are trimethoprim, sulphonamides,
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fosfomycin, and fusidic acid, which are mainly used in combination regimens for this reason. Several
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current projects focus on target-based discovery strategies with an associated risk of high-frequency
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single-step resistance with potentially rapid emergence of resistance during therapy [31]. A well-
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known example for rapid emergence of resistance during therapy is the inhibitor of leucyl-tRNA
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synthetase, GSK2251052, whose phase II trial for complicated UTIs was terminated due to high-level
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resistance seen after 1 day of treatment [32]. Key properties, such as very high potency (low MIC)
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and low toxicity to allow dosing at concentrations that kill bacterial cells with single-step mutations,
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may mitigate the risk in such drugs [16]. Combination therapy may be a way to circumvent this risk in
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clinical practice and should be included in the development strategy of such drugs. Currently used
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methods for studying the propensity for emergence of resistance are mostly sub-optimal [33]. A
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number of reviews have described a battery of systematic tests to predict the dynamics of
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spontaneous resistance evolution under well-controlled conditions [7,34-36]. An international panel
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of experts should agree on the most predictive tests to provide guidance for drug discovery.
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Stringent criteria for potency and toxicity as well as early testing for high-level single-step resistance
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in the discovery & development process should ensure that prioritised new drugs are not prone to
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rapid emergence of resistance, even during therapy.
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Conclusion
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Global policy initiatives are responding to rising resistance trends and recommending economic
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incentives to stimulate innovation in antibacterial discovery & development. The word ‘innovation’
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has not been appropriately defined for this specific context but has been used with a broad range of
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meanings. The definition of innovation will be central to prioritising reward strategies. The drug
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discovery community could contribute by using precise terms and reporting the characteristics of the
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compound in a clear and accurate way. As an overarching criterion, innovation could be defined
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functionally by focusing on the impact on resistance: a drug that lacks cross-resistance with existing
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drugs and has a low potential for high-frequency high-level single-step resistance. This view of
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innovation may require discovery strategies to adapt and include specific resistance-related studies
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early in the discovery process. An international, independent panel of experts should agree on the
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most predictive tests and detailed scientific criteria to define the biological aspects of innovation. The
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requirements for a lack of cross-resistance and low potential for emergence of one-step resistance
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can most likely be achieved by focusing on new chemical scaffolds, novel multi-molecular
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targets/novel binding sites and associated novel mode of action.
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Transparency declaration
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The author has no conflict of interest to disclose.
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Acknowledgment
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The author would like to thank Lynn Silver, Diarmaid Hughes, Robert Stavenger, Heinz Moser,
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Jennifer Leeds, Eric Bacque for their insightful comments and discussions.
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Funding
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The author received funding from the DRIVE-AB project (www.drive-ab.eu), which is supported by
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the Innovative Medicines Initiative (IMI) Joint Undertaking under grant agreement n°115618,
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resources of which are composed of financial contribution from the European Union’s Seventh
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Framework Programme (FP7/2007-2013) and EFPIA (European Federation of Pharmaceutical
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Industries and Associations) companies’ in kind contribution. DRIVE-AB is part of IMI’s New Drugs for
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Bad Bugs (ND4BB) programme.
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29. Silver LL. Multi-targeting by monotherapeutic antibacterials. Nat Rev Drug Discov 2007; 6:41-55.
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30. Brotz-Oesterhelt H, Brunner NA. How many modes of action should an antibiotic have? Curr
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Opin Pharmacol 2008;8:564-73.
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31. Silver LL. Appropriate Targets for Antibacterial Drugs. Cold Spring Harb Perspect Med 2016;6(12).
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ACCEPTED MANUSCRIPT 32. O'Dwyer K, Spivak AT, Ingraham K, et al. Bacterial Resistance to Leucyl-tRNA Synthetase Inhibitor
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GSK2251052 Develops during Treatment of Complicated Urinary Tract Infections. Antimicrob Agents
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Chemother 2015;59:289-98.
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33. Andersson DI. Improving predictions of the risk of resistance development against new and old
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antibiotics. Clin Microbiol Infect;21:894-8.
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34. Martinez JL, Baquero F, Andersson DI. Beyond serial passages: new methods for predicting the
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emergence of resistance to novel antibiotics. Curr Opin Pharmacol 2011;11:439-45.
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35. Chevereau G, Dravecka M, Batur T, et al. Quantifying the Determinants of Evolutionary Dynamics
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Leading to Drug Resistance. PLoS Biol 2015;13(11):e1002299.
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36. Martínez JL, Baquero F. Emergence and spread of antibiotic resistance: setting a parameter
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space. Ups J Med Sci 2014;119:68-77.
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ACCEPTED MANUSCRIPT Figure: Potential FDA approval of selected new antibiotics (systemic small molecules) according to their perceived innovation potential; attrition rates apply.
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old: modifications of currently used chemical scaffolds (human or animal health), new: new chemical scaffolds community: antibiotics targeted at community-acquired infections, usually focused on Gram-positive bacteria but also include respiratory pathogens and Neisseria gonorrhoea; oral formulations available ABSSTI: acute bacterial skin and soft tissue infections, usually focused on Gram-positive bacteria BLI: beta-lactamase inhibitor (vaborbactam, relebactam, avibactam, zidebactam, nacubactam, AAI202), aztreon+avibact: aztreonam+avibactam Pep.mi: Peptidomimetic, murepavadin for Pseudomonas aeruginosa FabI: FabI inhibitor specific for staphlococci Cephalosporins: cefiderocol, novel transport mechanism into the bacterial cell, potential for crossresistance not fully elucidated Aminoglycoside: plazomicin Fluoroquinolone: delafloxacin Tetracycline: eravacycline, omadacycline, TP-271 Pleuromutilin: lefamulin Macrolide (ketolide): nafithromycin Registered in Europe: fosfomycin, fusidic acid
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S1198-743X(17)30344-0
DOI:
10.1016/j.cmi.2017.06.020
Reference:
CMI 988
To appear in:
Clinical Microbiology and Infection
Received Date: 29 March 2017 Revised Date:
17 June 2017
Accepted Date: 19 June 2017
Please cite this article as: Theuretzbacher U, Antibiotic innovation for future public health needs, Clinical Microbiology and Infection (2017), doi: 10.1016/j.cmi.2017.06.020. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Antibiotic innovation for future public health needs
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Ursula Theuretzbacher
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Theme Issue
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Eckpergasse 13, 1180 Vienna, Austria
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[email protected]
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+436503801518
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Running title: Antibiotic innovation
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Center for Anti-Infective Agents
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Key words: antibiotic, discovery, innovation, cross-resistance, resistance
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Abstract
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Background: The public health threat of antibiotic resistance has gained attention at the highest
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political levels globally, and recommendations on how to respond are being considered for
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implementation. Among the recommended responses being explored for their feasibility is the
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introduction of economic incentives to promote research and development (R&D) of new antibiotics.
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There is broad agreement that public investment should stimulate innovation and be linked to
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policies promoting sustainable and equitable access to antibiotics. Though commonly used, the term
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‘innovation’ is not based on a common understanding.
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Aims: This article aims to initiate discussion on the meaning of ‘innovation’ in this context.
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Sources: Literature and expert opinion
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Content: As the definition of a novel class (novel scaffold, novel pharmacophore), a novel target
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(novel binding site) and a novel mode of action – the three traditional criteria for ‘innovation’ in this
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context – may be confounded by the complexities of antibacterial drug discovery, a biological and
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outcome-oriented definition of innovation is presented to initiate discussion. Such an expanded
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definition of innovation in this specific context is based on the overarching requirement that a drug
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not be affected by cross-resistance to existing drugs in the organisms and indications for which it is
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intended to be used, and that it have low potential for high-frequency, high-level single-step
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resistance if intended as a single drug therapy.
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Implications: Policy makers, public health authorities and funders could use such a comprehensive
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definition of innovation in order to prioritise where publicly funded incentives should be applied.
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Introduction
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Recent national and international high-level policy initiatives highlight the growing awareness of the
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increasing bacterial resistance to current antibiotics. This public health threat is receiving significant
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political attention. Multiple concerted actions concerning human and animal health, as well as
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ACCEPTED MANUSCRIPT pharmaceutical production and environmental sector policies, are recommended and need to be
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implemented. Considered urgent are: robust surveillance globally, responsible and optimized use of
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existing antibiotics, better infection control, increased research activities in the antibacterial field,
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restricting antibiotic use in animals, limiting antibiotic pollution of the environment, and economic
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incentives to stimulate and incentivize research, discovery and development of new antibacterial
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drugs to fill the neglected pipelines [1]. Such incentives will require substantial public investment.
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There is broad agreement that public investment should stimulate innovation and be linked to
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policies that promote sustainable and equitable access to antibiotics. The critically needed
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innovation in antibacterial drug discovery is expected to counteract the increasing trend of multidrug
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resistant (MDR), extensively drug resistant (XDR) and even pan-drug resistant (PDR) pathogens,
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especially Gram-negative bacteria as outlined in the recently published WHO priority pathogen list
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for R&D [2]. The often-used term ‘innovation’ has been used in a broad and indiscriminate way and
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has lost specific meaning. If policy initiatives are implemented, the requirement for innovativeness as
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a prioritisation tool needs to be discussed and defined. Europe’s Innovative Medicines Initiative (IMI)
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has financed a project, DRIVE-AB (i.e., Driving reinvestment in research and development for
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antibiotics and advocating their responsible use, www.drive-ab.eu), to provide scientific evidence for
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new reward models and to test the feasibility of their implementation [3]. If stimulating innovation in
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antibacterial drug discovery and development is to be a major factor of economic incentives, there is
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a need to reach a workable definition of ‘innovation’ and this is vital for matching public investment
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with future public health needs. As priority-setting requires a broad discussion and consensus
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considering the complexities of discovery, this article aims to initiate discussion on the meaning of
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‘innovation’ in this context. The discussion is focused on conventional, directly acting, antibacterial
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drugs that have not been used in human or veterinary medicine before worldwide. Other
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approaches, such as preventive strategies, immunomodulatory, adjunctive therapies that target
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virulence or resistance gene regulators, monoclonal antibodies, topical drugs and antibiotics against
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Mycobacterium tuberculosis, are not covered in this article.
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Current clinical antibiotic pipelines and short-term perspective
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Nearly all antibiotic classes we are using today were discovered during the Golden Age of antibiotic
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innovation, which extended from the 1940s to the 1960s [4]. Numerous modifications to the initial
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discoveries improved their utility and extended the life of these antibiotic classes. Efforts to modify
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the chemical structures were focused on circumventing emerging class-specific target-based or drug-
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modifying resistance mechanisms or on lower affinity for efflux pumps as well as improving
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pharmacokinetics and extending the activity spectrum. The beta-lactam class exemplifies best the
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success of this strategy. Methicillin and the isoxazolylpenicillins (Staphylococcal penicillins) were
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introduced following the rising frequency in resistance to penicillin due to the production of
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penicillinases. Third generation cephalosporins were introduced to solve the problem of beta-
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lactamases like TEM, ceftriaxone enabled a once-a-day dosing due to its extended half-life, and
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ceftazidime and ceftolozane included Pseudomonas aeruginosa in their Gram-negative spectrum.
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Despite these successes, the ever-increasing range of beta-lactamases required an alternative
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approach. The concept of a protector drug was born - the combination of vulnerable beta-lactams
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with a beta-lactamase inhibitor. After a great success of the combinations amoxicillin/clavulanic acid
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and piperacillin/tazobactam this concept has been revived and is still one direction of R&D efforts
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(Figure).
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The last years have seen a resurgence of discovery & development activities, mostly in small
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companies, often with the concept of modifying compounds in existing classes using cutting-edge
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methods to fix specific class-related resistance problems [5]. Basing a drug discovery project on a
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well validated lead carries less risk than starting from scratch. Most antibiotics in clinical
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development are modifications of classes that have been extensively used in human or animal health
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(Figure). The downside of modifying known chemical structures is that, usually, multiple mechanisms
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of resistance exist for every class of antibiotics and not all relevant resistance mechanisms can be
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addressed by chemical modification. Some cross-resistance to existing antibiotics usually remains.
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Thus, due to the selection of less common resistance mechanisms or the appearance of previously
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ACCEPTED MANUSCRIPT unknown ones [6,7] modifications within existing antibiotic classes may only buy some time [8]. In
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the long run, innovation is needed to find novel drugs without pre-existing cross-resistance that can
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be further improved in future efforts.
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How to define innovation?
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Although there is general agreement that we need ’innovation’ in antibiotic R&D to respond now to
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anticipated future medical needs, the lack of clarity around ’innovation’ itself presents a challenge.
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The word innovation is one of the most commonly used terms in national and international initiatives
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that address the antibiotic resistance problem, but what is meant by ‘innovation’ or how different
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stakeholders interpret the term is unclear. In the context of stimulating the discovery of novel
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antibiotics that can address the most resistant pathogens and meet anticipated future public health
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needs, policy makers and public health authorities need a workable definition of innovation in order
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to prioritise incentives to be underwritten with public funds.
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Discovery programmes may take 15 years or longer [9]. Therefore, when defining innovation in this
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context, it is essential to consider longer-term resistance trends, scientific challenges, and the most
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urgent anticipated public health needs. Innovation is commonly associated with a novel antibiotic
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class, a novel target (binding site) or a novel mode of action. However, these terms are not clearly
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defined and are open to broad interpretation. Some aspects of these terms are discussed below
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before suggesting additional criteria.
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Novel antibiotic class
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Antibiotics are historically grouped into antibacterial classes. The classes are defined according to the
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active chemical scaffold (e.g. ß-lactams, fluoroquinolones) or functional aspects (e.g. topoisomerase
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inhibitors, beta-lactamase inhibitors). Chemical classes are groupings that relate compounds by
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similar features, usually by their active chemical structure (pharmacophore). Assignment of a new 5
ACCEPTED MANUSCRIPT compound to an antibacterial class or subclass is sometimes influenced by marketing considerations
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and the desire to differentiate a drug from existing ones. Creating new classes or subclasses may be
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an appealing way to influence user perception. An example is the glycyl derivative of minocycline,
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tigecycline, which is a member of the tetracycline chemical class but was described as the first
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member of a new class called glycylcyclines [10]. Another example is the ketolide class, which was
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created many years ago for telithromycin because it contains a keto function [11]. The ketolide
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classification fell out of favour after evidence of the toxicity of telithromycin emerged, and later
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derivatives were preferably associated with the macrolide class to prevent the association with
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toxicity. Classifying new drugs may be a longer process until agreement is achieved as no rules exist
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and terminology may change. Fluoroquinolones are grouped according to their chemical core
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structure and their ability to inhibit the essential bacterial enzymes DNA gyrase and topoisomerase
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IV. A new group of antibiotics with a different chemical scaffold also inhibits DNA gyrase and
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topoisomerase IV with a different mode of action [12]. They are called Novel Bacterial type II
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Topisomerase Inhibitors, thus grouped according to their function. This is a recent example of the
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creation of a new class of antibiotics based on functional and not chemical aspects. These examples
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show that there is no clear and broadly accepted definition of what constitutes a novel antibacterial
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class. A more precise term would be a new active chemical structure, scaffold or pharmacophore. To
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complicate things further, the concept of a novel antibacterial class as a major pillar of innovation
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may not be sufficient for future XDR and PDR pathogens. Even novel chemical scaffolds that are not
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used in existing antibiotics may show cross-resistance (also called co-resistance) with unrelated
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structures in cases where they share overlapping binding sites on the same bacterial target or are
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affected by unspecific resistance mechanisms such as efflux.
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Novel bacterial target
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When it comes to meeting the test of innovation through a novel bacterial target, criteria for a ‘new
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target’ may be too vague, as the term ‘target’ is not defined and may be complicated by the
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existence of more than one specific binding site. Besides the definition of a binding site a target is
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ACCEPTED MANUSCRIPT often perceived to be a functional structure, such as the ribosome or the cell wall. The ribosome
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target has been exploited extensively over the history of antibiotics, as it has multiple binding sites
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which are used by many antibiotics of different chemical scaffolds. The recent advances that X-ray
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crystallography has brought to the understanding of the structure and function of the ribosome has
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revealed the molecular details of the various antibiotic-binding sites [13]. Some of these binding sites
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are in close proximity and may be overlapping. If a resistance mechanism affects a specific binding
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site, all different chemical scaffolds that share this binding site may be affected. Well-known
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examples are MLSB-resistance affecting macrolides, lincosamides, and streptogramin B or PhLOPSA-
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resistance based on the cfr gene (RNA methyltransferase) and affecting phenicols, lincosamides,
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oxazolidinones, pleuromutilins, and streptogramin A.
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Specific cases that highlight the difficulties to classify a drug as novel include antibiotics with targets
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that have not been used in human medicine for systemic infections but in other fields. This includes
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lefamulin, a drug in phase 3 clinical development. It belongs to the class of pleuromutilins that have a
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long record in the field of animal farming (tiamulin/valnemulin) but also topical human use for
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superficial skin infections (retapamulin). Though targeting different pathogens in veterinary medicine
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the impact of possible exchange of resistance determinants between bacterial species and longer-
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term influence of prior and current use on the development of resistance in human health is not
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known [14]. Transferable resistance to pleuromutilins due to vga genes has emerged globally in
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livestock-associated MRSA [15]. Another example is the functional class of FabI inhibitors, with one
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drug in active clinical development for the treatment of staphylococcal infections, as well as the non-
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specific biocide and slow-binding FabI inhibitor triclosan. Due to its dual mode of action triclosan has
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been widely used as a disinfectant in consumer products and point mutations in the FabI target site
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of staphylococci are well described [15,16]. Selection pressure due to triclosan use may have been
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exerted before the introduction of the new FabI inhibitors in clinical trials for the systemic treatment
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of staphylococcal infections.
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ACCEPTED MANUSCRIPT Novel mode of action
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The ‘mode of action’ is often complex not always understood at early phases of discovery and
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development and the term is rather vague. It has been used in a general functional way, for instance
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to identify topoisomerase inhibitors by the fact that they inhibit DNA replication. Molecular details of
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how these drugs interact with their target have only recently been described [17]. For many
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antibiotics, especially the natural products, the mode of action may be complex and may not be
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entirely revealed until they are widely used. Different affinities for primary and secondary binding
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sites may influence the terminology. Additionally, different chemical solutions may bring about
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analogous features of mechanisms of action as has been shown for some cationic antimicrobial
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peptides and anionic lipopetides such as daptomycin [18,19]. The mode of action describes the sum
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of all effects that an antibacterial agent exerts in/at a cell. Such complex and pleiotropic effects may
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not be deciphered early on. Therefore, basing the concept of innovation solely on “mode of action”
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may not be sufficient and should be expanded to additional criteria.
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A biological approach
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As shown in the sections above, what is meant by a novel class, novel target or novel mode of action
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is not clear, especially in the context of resistance. All that matters for treating patients with MDR,
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XDR or PDR pathogens is having antibiotics available to which these highly resistant pathogens are
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reliably susceptible. As the currently used terminology is diffuse adding a biological definition of
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innovation may be more meaningful. A biological definition of innovation in the above-described
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context is based on the requirement that a drug not be affected by cross-resistance to existing drugs
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in the organisms for which it is intended to be used, and that it have low potential for high-
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frequency, high-level single-step resistance. This definition of innovation would satisfy the need for
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prioritising novel antibiotics against the most resistant pathogens that are expected to burden
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patients and health care systems even more in the future.
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Cross-resistance occurs when resistance to a specific drug influences susceptibility and resistance to
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other antibiotics simultaneously [20]. This is a well-known phenomenon for antibiotics within the
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same class; for example, the acquisition of extended spectrum beta-lactamases (ESBL) caused cross-
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resistance within the class of penicillins, cephalosporins and monobactams. Recent modifications of
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known antibiotic classes commonly address such class-specific resistance mechanisms. Plazomicin, a
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derivative of the aminoglycoside sisomicin was designed to resist modification by most
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aminoglycoside-modifying enzymes [21]. Although this is the most common resistance mechanism,
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target resistance due to modification mediated by ribosomal methyltranferases may equate to cross-
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resistance to other aminoglycosides. The epidemiology of specific resistance mechanisms determines
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the clinical relevance of the cross-resistance. For example, eravacycline, a new synthetic tetracycline,
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shows an overlapping MIC distribution with tigecycline among the enterobacteriaceae and
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Acinetobacter baumanii. Though demonstrating mostly 2-4 fold lower MICs, eravacycline MICs reflect
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the rise of tigecycline MICs above the susceptibility breakpoint, thus, leading to close correlation
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between MICs of both molecules and demonstrating a significant level of cross-resistance with
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tigecycline [22].
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Cross-resistance may extend beyond class-specific resistance. Non-specific resistance mechanisms
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can confer resistance (also called co-resistance) to antibiotics of different classes [23]. Well-known
206
examples are mutations that alter the expression of efflux pumps or cell wall porins [24] and affect
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several unrelated antibiotics. It has been recently shown that reduced eravacycline and tigecycline
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susceptibility in a subset of carbapenem-resistant KPC-producing Klebsiella pneumoniae isolates is
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most likely due to upregulated efflux pumps [22,25]. A newly approved antibacterial product,
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ceftazidime/avibactam, was developed to escape the degradation by more beta-lactamases than
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existing beta-lactamase inhibitor combinations. Although the spectrum of beta-lactamases that are
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inhibited by avibactam is extended, some of the most resistant pathogens, such as MDR
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Pseudomonas aeruginosa [26], may still survive by a combination of the effects of increased drug
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ACCEPTED MANUSCRIPT efflux and decreased cell permeability. Testing a new drug candidate early on against a panel of XDR
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clinical as well as genetically defined strains would be most important [27].
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Low potential for rapid resistance evolution
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Innovative novel drugs that inhibit a single molecular target or a target that can be bypassed easily
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have a high potential for rapid resistance evolution [13, 28-30]. A single mutation in the target-
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determining gene can lead to single-step high-level resistance with potentially rapid emergence of
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resistance during therapy. Examples of old single-target drugs are trimethoprim, sulphonamides,
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fosfomycin, and fusidic acid, which are mainly used in combination regimens for this reason. Several
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current projects focus on target-based discovery strategies with an associated risk of high-frequency
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single-step resistance with potentially rapid emergence of resistance during therapy [31]. A well-
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known example for rapid emergence of resistance during therapy is the inhibitor of leucyl-tRNA
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synthetase, GSK2251052, whose phase II trial for complicated UTIs was terminated due to high-level
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resistance seen after 1 day of treatment [32]. Key properties, such as very high potency (low MIC)
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and low toxicity to allow dosing at concentrations that kill bacterial cells with single-step mutations,
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may mitigate the risk in such drugs [16]. Combination therapy may be a way to circumvent this risk in
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clinical practice and should be included in the development strategy of such drugs. Currently used
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methods for studying the propensity for emergence of resistance are mostly sub-optimal [33]. A
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number of reviews have described a battery of systematic tests to predict the dynamics of
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spontaneous resistance evolution under well-controlled conditions [7,34-36]. An international panel
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of experts should agree on the most predictive tests to provide guidance for drug discovery.
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Stringent criteria for potency and toxicity as well as early testing for high-level single-step resistance
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in the discovery & development process should ensure that prioritised new drugs are not prone to
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rapid emergence of resistance, even during therapy.
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Conclusion
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Global policy initiatives are responding to rising resistance trends and recommending economic
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incentives to stimulate innovation in antibacterial discovery & development. The word ‘innovation’
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has not been appropriately defined for this specific context but has been used with a broad range of
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meanings. The definition of innovation will be central to prioritising reward strategies. The drug
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discovery community could contribute by using precise terms and reporting the characteristics of the
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compound in a clear and accurate way. As an overarching criterion, innovation could be defined
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functionally by focusing on the impact on resistance: a drug that lacks cross-resistance with existing
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drugs and has a low potential for high-frequency high-level single-step resistance. This view of
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innovation may require discovery strategies to adapt and include specific resistance-related studies
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early in the discovery process. An international, independent panel of experts should agree on the
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most predictive tests and detailed scientific criteria to define the biological aspects of innovation. The
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requirements for a lack of cross-resistance and low potential for emergence of one-step resistance
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can most likely be achieved by focusing on new chemical scaffolds, novel multi-molecular
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targets/novel binding sites and associated novel mode of action.
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Transparency declaration
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The author has no conflict of interest to disclose.
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Acknowledgment
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The author would like to thank Lynn Silver, Diarmaid Hughes, Robert Stavenger, Heinz Moser,
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Jennifer Leeds, Eric Bacque for their insightful comments and discussions.
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Funding
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The author received funding from the DRIVE-AB project (www.drive-ab.eu), which is supported by
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the Innovative Medicines Initiative (IMI) Joint Undertaking under grant agreement n°115618,
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resources of which are composed of financial contribution from the European Union’s Seventh
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Framework Programme (FP7/2007-2013) and EFPIA (European Federation of Pharmaceutical
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Industries and Associations) companies’ in kind contribution. DRIVE-AB is part of IMI’s New Drugs for
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Bad Bugs (ND4BB) programme.
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ACCEPTED MANUSCRIPT Figure: Potential FDA approval of selected new antibiotics (systemic small molecules) according to their perceived innovation potential; attrition rates apply.
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old: modifications of currently used chemical scaffolds (human or animal health), new: new chemical scaffolds community: antibiotics targeted at community-acquired infections, usually focused on Gram-positive bacteria but also include respiratory pathogens and Neisseria gonorrhoea; oral formulations available ABSSTI: acute bacterial skin and soft tissue infections, usually focused on Gram-positive bacteria BLI: beta-lactamase inhibitor (vaborbactam, relebactam, avibactam, zidebactam, nacubactam, AAI202), aztreon+avibact: aztreonam+avibactam Pep.mi: Peptidomimetic, murepavadin for Pseudomonas aeruginosa FabI: FabI inhibitor specific for staphlococci Cephalosporins: cefiderocol, novel transport mechanism into the bacterial cell, potential for crossresistance not fully elucidated Aminoglycoside: plazomicin Fluoroquinolone: delafloxacin Tetracycline: eravacycline, omadacycline, TP-271 Pleuromutilin: lefamulin Macrolide (ketolide): nafithromycin Registered in Europe: fosfomycin, fusidic acid
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