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Recent advances in the treatment of Gram-positive infections
Vol. 1, No. 4 2004
Drug Discovery Today: Therapeutic Strategies Editors-in-Chief Raymond Baker – formerly University of Southampton, UK and Merck Sharp & Dohme, UK Eliot Ohlstein – GlaxoSmithKline, USA DRUG DISCOVERY
TODAY THERAPEUTIC
STRATEGIES
Infectious diseases
Recent advances in the treatment of Gram-positive infections Ken Coleman Infection Discovery, Cancer and Infection Research Area, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA
Gram-positive bacteria lack many of the complex permeation and export pathways found in Gram-negative bacteria, making them usually more amenable to antibacterial therapy. Yet, despite this, resistance to antibacterial agents is a widespread and growing problem among most of the major Gram-positive pathogens, with multi-resistant organisms now commonly encountered in the outpatient community as well as the hospital. What is the future for the treatment of Gram-positive pathogens?
Introduction Gram-positive bacteria are responsible for a wide range of diseases [1], and rising antibiotic resistance in this group is causing increasing concern. In the 1940s, Streptococcus pneumoniae, a common community respiratory pathogen, was the cause of large numbers of pneumonia-related deaths. The mortality rate fell dramatically with the advent of antibiotics, but S. pneumoniae resistance rates are now increasing [2] with a concomitant increase in mortality [3]. The quinolones are the only class still active against the majority of strains, but resistance to them is rising [4,5]. The recent spread of new multi-drug resistant variants of Staphylococcus aureus in the hospital and community [6] is causing similar concern [7]. This review describes novel agents and alternative approaches that might provide the means to address these resistance issues in the foreseeable future.
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DOI: 10.1016/j.ddstr.2004.08.015
Section Editor: Gary Woodnutt – Diversa Corp., San Diego, CA, USA Bacterial resistance is an increasing concern globally. In particular, all of the important Gram-positive pathogens (Enterococci, Staphylococci, Streptococci) are resistant to multiple agents. Research activities are attempting to define new targets that will be important for inhibitor targeting as well as vaccine development, but these are many years away from being realized clinically. However, several compounds are in development, some of which address new targets (e.g. ramoplanin, daptomycin, and peptide deformylase inhibitors), but most are either product-line extensions (e.g. Augmentin) or new generation compounds that incrementally address some of the resistance issues (e.g. quinolones, b-lactams, and glycopeptides). Targeting of the resistance mechanisms (e.g. efflux or b-lactamase inhibitors) also appears to be a viable opportunity for more combination agents. This review discusses the potential for these agents and questions whether we are in a position to continue to win the battle against the continuous evolution of these important organisms.
Key strategies for the treatment of Gram-positive infections Refer to Table 1 for a summary of the key strategies discussed below.
Best-in-class antibacterials Many of the older antibacterial classes still have some mileage in them, and most of the compounds currently in development (see Supplementary Table 1) are derived from old classes. A huge body of knowledge has been built up around these classes over the years, yielding insights into relationships between chemical structure and biological properties. Such insights can guide the chemist to improve the clinical utility of novel members of the class and diminish the challenge of building drug-like properties (e.g. solubility and www.drugdiscoverytoday.com
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There are good arguments both ways here. Broad-spectrum agents can be used to treat patient symptoms before diagnostic results are available (Pro), but also compromise the host’s normal flora (Con). Narrow spectrum agents do not cause collateral damage to the normal flora (Pro), but multiple medications are required for broad cover (Con). For the purposes of this table, the term broad-spectrum means active against a range of Gram-positive species but does not exclude the possibility of Gram-negative activity as well. Narrow-spectrum means active against a single Gram-positive species or, in the case of attenuation of virulence, a limited range of species. b For a more detailed list of compounds, etc. in development refer to Supplementary Table 1.
a
Quorex (http://www.quorex.com/) No longer in this area Numerous other companies have looked Inhibitors of quorum sensing systems
(Development discontinued?)
Probably requires special diagnostics Could require concomitant use of antibacterial drugs Commensal friendly Attenuation of virulence
Narrow-spectrum
Daiichi (http://www.daiichi.com/) Efflux pump inhibitor (Gram-negative) for combination with quinolone. (Development discontinued?) Extend useful life of existing drugs Inhibition of resistance
Should reduce antibiotic use
Broad-spectrum
Not amenable to most drug classes Nothing since 1980s (b-lactamase inhibitors)
Nabi (http://www.nabi.com/) StaphVax (Phase 2: Launch 2005)
Antigenics (http://www.antigenics.com/) Quillimune-P (Phase 2: Launch 2006)
Replacement by non-vaccine serotypes Immunocompromised patients Early trials promising Vaccines
Narrow-spectrum
Daptomycin (Launched 2003) BB-83698 (Phase 1: Launch unknown) New technology Scaffolds often undruglike No resistance Registration might be easier
Broad-spectrum
Cons Pro and con?a
First-in-class
The tetracyclines have been compromised by widespread resistance, but two novel intravenous glycylcyclines, tigecy-
Numerous classes Much is known Drugable scaffold
Glycylcyclines (broad-spectrum, intravenous)
Best-in-class
The earlier quinolones had weak Gram-positive activity, but gatifloxacin (Bristol–Myers Squibb http://www.bms.com/) and moxifloxacin (Bayer http://www.bayer.com/) are two newer market entries that have largely addressed this issue. Garenoxacin (Toyama http://www.toyama-chemical.co.jp/ and Schering-Plough http://www.sch-plough.com/) and DX 619 (Daiichi Seiyaku http://www.daiichipharm.co.jp/) are two development quinolones, which appear to have extremely potent in vitro activity against Gram-positive organisms, including many which are resistant to other quinolones [10,11].
Pros
Quinolones (broad-spectrum, oral and intravenous)
Strategy
The market leaders in the class are the intravenous, hospital broad-spectrum agents ceftriaxone (no pseudomonas activity; dosed u.i.d) and ceftazidime (pseudomonas activity; dosed b.i.d). The major weakness of the class is a lack of activity against methicillin-resistant staphylococci (MRSA), and many of the cephalosporins currently in development claim utility against MRSA. Three intravenous and two oral cephalosporins are currently under development, focused mainly on hospital broad spectrum, most lacking pseudomonas activity.
Table 1. Comparison of the different Gram-positive treatment strategies
Cephalosporins (broad-spectrum, oral and intravenous)
Doripenem (Pre-reg: Launch 2004) Tigecycline (Phase 3: Launch 2004)
Latest developmentsb
The market leaders in this class are imipenem and meropenem, which are intravenous agents whose broad spectrum includes the Gram-negative organism Pseudomonas. A recent entry, ertapenem, is intravenous but lacks activity against Pseudomonas. R 115685 [8] (Roche; http://www.roche.com/ licensed from Sankyo; http://www.sankyo.co.jp/) and doripenem [9] (Shionogi; http://www.shionogi.co.jp/) are intravenous carbapenems aimed at the imipenem market. Peninsula (http:// www.peninsulapharm.com/) has in-licensed doripenem for some markets and is developing an inhaled formulation focused on cystic fibrosis. Tebipenem (Meiji-Seika; http:// www.meiji.co.jp/) is oral but lacks activityagainst Pseudomonas.
Resistance is widespread
Carbapenems (broad-spectrum, oral and intravenous)
Broad-spectrum
Who is working on this strategy?
bioavailability) into the molecule because they are already present in closely related existing drugs. On the downside, new compounds will be launched into an environment where widespread resistance already exists and cost-conscious healthcare policies often make it difficult to establish new agents in the market with only incremental improvements in potency, spectrum, pharmacokinetics or safety. Some of the major classes of novel agents currently in development are reviewed here and summarized in the Supplementary Table 1.
Cubist (http://www.cubist.com/) Oscient (http://www.oscient.com/)
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Shionogi (http://www.shionogi.co.jp/) Wyeth (http://www.wyeth.com/)
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cline [12,13] (Wyeth http://www.wyeth.com/) and PTK 0796 [14,15] (BAY-73-6944; Paratek http://www.paratekpharm.com/ licensed to Bayer) are not affected by the majority of these resistance mechanisms and have broad-spectrum activity, including activity against MRSA and VRE [15,16]. Ketolides (broad-spectrum, oral and intravenous)
Cethromycin (ABT-773) is a broad-spectrum, oral ketolide [17]. Abbott (http://www.abbott.com/) discontinued Phase 3 studies in 2002, although Taisho (http://www.taisho.co.jp/) have continued development in Japan. Several other companies (Chiron http://www.chiron.com/, Enanta http://www. enanta.com/, Pfizer http://www.pfizer.com/, Johnson & Johnson http://www.jnj.com/) are known to have ketolide programs at a pre-clinical stage.
First-in-class The easiest way to circumvent existing resistance mechanisms is to develop agents that inhibit novel targets, because it can generally be assumed that these will be launched into an environment lacking organisms with pre-existing targetbased resistance. In the past 15 years, rapid advances in genomics, genetics, chemistry, and automation have enabled the implementation of sophisticated, large-scale, target-based screens. The 1990s saw several companies rushing into genome-based, high-throughput antibacterial screening, and, for a variety of reasons, the 2000s have seen many of them rushing out again [18]! Although many of the essential single targets found in important clinical bacteria have been extensively screened, the current development pipeline contains few novel first-in-class compounds. So what has gone wrong? It is fair to say that the implementation path for this new screening paradigm has been littered with problems, many of which are only now reaching resolution (see Box 1 for examples of some of the chemistry-related issues). For a crucial review of the issues as they apply to modern drug research, refer to [19] and for an excellent infection-focused review, refer to [20]. Glycopeptide-like agents (Gram-positive only, intravenous only)
A class of bactericidal cell wall inhibitors, with vancomycin the market leader in the class, although vancomycin-resistance is now common among enterococci (VRE) and is appearing in staphylococci. Several compounds are in development or have recently been launched which are derived from natural products and act at targets close to that of vancomycin. All are intravenous, Gram-positive only agents. Last year saw the launch of daptomycin [21,22] (Cubist http://www.cubist.com/), a lipoglycopeptide that maintains activity against VRE. Four other glycopeptides or glycopeptide-like compounds are currently under development, most of which claim activity against VRE. Of these, dalbavancin
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Box 1. Struggling with compound diversity Many high-throughput screening campaigns result either in no hits worth pursuing or in highly lipophilic hits. Lipophilic molecules tend to be poorly soluble and highly serum bound, two features that need to be engineered out of the molecule to make it drug-like. Too often, however, biological activity is closely correlated with lipophilicity, so the more drug-like the molecule becomes, the less active it becomes. This is one of the principal reasons for the limited success seen so far in all therapy areas with target-based screening, and much thought has gone into what constitutes a good lead-generating library (see, e.g. Ref. [44]). Some would argue that this high failure rate reflects a lack of chemical diversity within compound collections. Expanding chemical diversity has been a high priority for pharmaceutical companies for several years and is still one the industry is struggling to address. With the advent of automation and miniaturization came combinatorial chemistry, which, for a while, promised a cost-effective way of building large, diversified compound libraries. So far, however, the promise remains largely unfulfilled [45]. There is also a drive for diversity through introducing large-scale natural product collections into compound banks [46] and some companies are once more trying to exploit natural products through the engineering of biosynthetic pathways (e.g. Kosan http://www.kosan.com/). It is certainly true that marketed antibacterials derived from natural products have a level of chemical complexity that is lacking from many compound collections and from marketed synthetic antibacterials [47].
[22,23] (Versicor http://www.vicuron.com/) has the distinction of once per week dosing, whereas oritavancin [13,22] (Intermune http://www.intermune.com/) and telavancin (Theravance http://www.theravance.com/) are dosed once daily. Ramoplanin [22] (Oscient http://www.oscient.com/) cannot be dosed intravenously and is under development for large bowel disinfection of Clostridium difficile and VRE. Recent intelligence suggests that development of oritavancin has terminated. Pepetide deformylase inhibitors (broad-spectrum, oral and intravenous)
These are the only truly novel agents known to be in development at present that are derived from genome-based target selection. Unfortunately, the high resistance rates observed in S. aureus and Escherichia coli are probable to limit the use of this series to community respiratory agents [22]. Oscient have taken one PDF inhibitor into man [24]; this compound lacked activity against Haemophilus influenzae, limiting its use as a respiratory antibacterial, but did show good human pharmacokinetics. Oscient are continuing to work on this series. Vicuron are also actively pursuing PDF inhibitors and one compound [25] has been licensed to Novartis (http:// www.novartis.com/) and is in Phase 1. Many other classes of compound derived from target-based screening are in late-stage discovery and have not yet moved into development. These include tRNA synthetase inhibitors [26,27] and inhibitors of fatty acid biosynthesis [28,29]. www.drugdiscoverytoday.com
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For a more comprehensive review of novel best-in-class and first-in-class Gram-positive agents in development, refer to the recent reviews [22,30,31].
Vaccines Vaccines have been used for the prevention of pneumococcal disease for almost a century but, until recently, have had limited success in those most at risk, the very young, the very old and the immunocompromised. Prevnar1 (Wyeth), the first protein-conjugated pneumococcal vaccine, was licensed in the USA in 2000 for routine use in children under two years old, and is the first to provide lasting protection to the very young [32]. In trials, it has shown a 93% reduction in invasive pneumococcal disease and a 73% reduction in consolidated pneumonia [33]. One interesting result of effective vaccination is indirect immunity or the herd ‘effect’, whereby pneumococcal infections in the unvaccinated are reduced owing to the presence of a vaccinated population [34]. Vaccination has significantly reduced the nasopharyngeal carriage of vaccine serotypes, but there is a simultaneous increase in the carriage rates of non-vaccine-serotypes [35]. This, plus the variation in serovars seen from country to country, has driven the development of vaccines of increasing valency, such as the 23-valent Quilimmune-P1 (Antigenics http://www.antigenic.com/). Undoubtedly, widespread use of these new S. pneumoniae vaccines, along with similarly effective vaccines against the Gram-negative pathogens H. influenzae and Neisseria meningitidis, should reduce the incidence of infection, and hence the use of antibacterials, in the young. A new entry in this area is StaphVAX1 (Nabi http:// www.nabi.com/), a vaccine directed at S. aureus capsular types 5 and 8, which together account for 80–90% of S. aureus clinical infections. The vaccine is in Phase III trials in kidney patients receiving peritoneal dialysis, a population at high risk from serious staphylococcal infection [36].
Inhibition of resistance mechanisms The strategy of partnering a b-lactam antibiotic with an agent that inhibits the more common b-lactam-inactivating enzymes has proven successful in the past, with AugmentinTM (GSK http://www.gsk.com/) and ZosynTM (Wyeth) the best commercial examples of the strategy. Despite a large effort in this area in the 1990s [37], no new combinations have appeared during the past 20 years, although there are a few novel b-lactamase inhibitors in pre-development [38]. Unfortunately, this approach seems unlikely to be successful for antibiotic classes other than b-lactams [39,40]. For many classes, resistance is mediated either by target mutation, target modification or altered metabolic pathway, where combination therapy is inappropriate and novel scaffolds with different target binding properties are the best way to address resistance. 458
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Enzymatic modification of the drug is another major mechanism of resistance and, for most drug classes, a wide range of enzymes are employed, necessitating a combination with multiple inhibitors and making both discovery and development high risk. The exception is the chloramphenicols, which are metabolized by a single class of enzymes [40]. Chloramphenicols have serious safety problems, however, and the higher regulatory hurdles in place today make it unlikely that a combination drug could be launched from this class. Many antibacterials are subject to efflux, and combining an antibiotic with an efflux pump inhibitor has been an elusive holy grail for some time [41]. Our understanding of these pumps is improving now that crystal structures are becoming available [42] but, so far, this strategy has not proved successful. An alternative strategy to inhibition of efflux pumps is the development of agents that are not subject to the efflux problems of earlier members of a series; an approach that has proved successful for tigecycline and PTK 0796 (mentioned above).
Attenuation of virulence Antibacterial agents arising from a first-in-class or best-inclass strategy cure by killing or inhibiting growth of the invading organism in the patient. A disadvantage of this method is the collateral death of many non-pathogenic organisms residing on and in the host, sometimes with unpleasant side effects (e.g. antibiotic-associated diarrhea).
Box 2. Some questions surrounding inhibition of virulence factors Many virulence factors are switched on in response to some signal from the host and are not present in cells growing on conventional laboratory media. This rules out standard in vitro testing, which makes the discovery process more arduous and means that a special diagnostic test must be launched simultaneously with any new drug, thus raising costs significantly. How will clinical laboratories assess susceptibility to these agents and, perhaps more importantly, the inevitable development of resistance to them? Most current animal models of infection utilize a lethal dose of infecting organism and look for rapid clearance of the infection. Colonization models, much less severe and much less reproducible, would be required for the evaluation of anti-virulence agents, and few exist at present. How can these models best be developed? Many infections require the pathogen to produce a variety of factors at different stages of the disease. Will the inhibition of a single factor be effective? How will such drugs be utilized; as prophylactics for high-risk patients, in combination with an antibacterial agent or as mono-therapy? How can these agents best be evaluated for registration?
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Bacteria produce virulence factors to enable host colonization and their inhibition could be considered a target for antimicrobial chemotherapy [43]. This type of chemical intervention would not be expected to have such a profound effect on the normal host flora because many virulence factors are found in a limited number of pathogens. But developing inhibitors of this type is no easy task. Although this strategy looks extremely promising at first sight, there remain many issues to address (see Box 2 for a partial list of unanswered questions) and there are signs that the initial enthusiasm for this approach is fading. As an example, Quorex (http:// www.quorex.com/), a company exclusively focused on this strategy from its inception, shifted to a first-in-class strategy in 2002.
isms. Within this strategy, the inhibition of bacterial broadspectrum efflux pumps probably has the greatest chance of success, but the complex structure and the multitude of binding sites in these pumps has so far defeated all comers. Meanwhile, antibiotic resistance continues to increase, sometimes at an alarming rate, and the race to keep up has been likened [22] to a quote from the Red Queen in Lewis Carroll’s book Alice Through The Looking Glass: ‘‘Now, here, you see, it takes all the running you can do, to keep in the same place.’’ Let us hope that we can slow the pace down using some of the strategies outlined here!
Conclusions
Supplementary data associated with this article can be found, in the online version, at 10.1016/j.ddstr.2004.08.015.
Three antibiotic classes, b-lactams, macrolides, and quinolones, have been the mainstays of infection therapy for the past 30 years or more and, judging from current development pipelines, look set to remain so for the immediate future. Unfortunately, the resistance mechanisms already present in community and hospital environments mean that most new compounds from these classes are likely to be compromised to some extent before they are even launched. The major exceptions could be the glycylcyclines (e.g. tigecycline), which seem to have overcome most of the major Grampositive tetracycline resistance mechanisms, and some of the glycopeptide-like agents (e.g. daptomycin), which inhibit targets close to that of vancomycin but maintain activity against vancomycin-resistant strains. The other strategies outlined in this review have not, so far, met with the same success as the best-in-class strategy. The plethora of novel antibacterial targets reported over the past 10 years have so far produced little to fill the antibiotic pipeline, although the recent Phase 1 trials of two peptide deformylase inhibitors might be the first signs that the genomically-driven, target-based screening approach is beginning to bear fruit. Let us hope that we see many more first-in-class agents in development in the near future. The new breed of protein-conjugated vaccines is already having an impact on respiratory infections in the young and might reduce the need for antibiotic intervention in this population. Whether they will be as successful in other indications and populations remains to be seen. No compound based on the strategy of inhibiting virulence factors has entered development as yet, and we must await the first of these to progress into human before we have answers to many of the fascinating questions posed by this approach. Finally, the inhibition of resistance mechanisms to existing antibiotic classes, which proved so successful for the penicillins, is unlikely to be a viable strategy for any other class due mainly to the multi-factorial nature of these mechan-
Appendix A. Supplementary data
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Drug Discovery Today: Therapeutic Strategies Editors-in-Chief Raymond Baker – formerly University of Southampton, UK and Merck Sharp & Dohme, UK Eliot Ohlstein – GlaxoSmithKline, USA DRUG DISCOVERY
TODAY THERAPEUTIC
STRATEGIES
Infectious diseases
Recent advances in the treatment of Gram-positive infections Ken Coleman Infection Discovery, Cancer and Infection Research Area, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA
Gram-positive bacteria lack many of the complex permeation and export pathways found in Gram-negative bacteria, making them usually more amenable to antibacterial therapy. Yet, despite this, resistance to antibacterial agents is a widespread and growing problem among most of the major Gram-positive pathogens, with multi-resistant organisms now commonly encountered in the outpatient community as well as the hospital. What is the future for the treatment of Gram-positive pathogens?
Introduction Gram-positive bacteria are responsible for a wide range of diseases [1], and rising antibiotic resistance in this group is causing increasing concern. In the 1940s, Streptococcus pneumoniae, a common community respiratory pathogen, was the cause of large numbers of pneumonia-related deaths. The mortality rate fell dramatically with the advent of antibiotics, but S. pneumoniae resistance rates are now increasing [2] with a concomitant increase in mortality [3]. The quinolones are the only class still active against the majority of strains, but resistance to them is rising [4,5]. The recent spread of new multi-drug resistant variants of Staphylococcus aureus in the hospital and community [6] is causing similar concern [7]. This review describes novel agents and alternative approaches that might provide the means to address these resistance issues in the foreseeable future.
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DOI: 10.1016/j.ddstr.2004.08.015
Section Editor: Gary Woodnutt – Diversa Corp., San Diego, CA, USA Bacterial resistance is an increasing concern globally. In particular, all of the important Gram-positive pathogens (Enterococci, Staphylococci, Streptococci) are resistant to multiple agents. Research activities are attempting to define new targets that will be important for inhibitor targeting as well as vaccine development, but these are many years away from being realized clinically. However, several compounds are in development, some of which address new targets (e.g. ramoplanin, daptomycin, and peptide deformylase inhibitors), but most are either product-line extensions (e.g. Augmentin) or new generation compounds that incrementally address some of the resistance issues (e.g. quinolones, b-lactams, and glycopeptides). Targeting of the resistance mechanisms (e.g. efflux or b-lactamase inhibitors) also appears to be a viable opportunity for more combination agents. This review discusses the potential for these agents and questions whether we are in a position to continue to win the battle against the continuous evolution of these important organisms.
Key strategies for the treatment of Gram-positive infections Refer to Table 1 for a summary of the key strategies discussed below.
Best-in-class antibacterials Many of the older antibacterial classes still have some mileage in them, and most of the compounds currently in development (see Supplementary Table 1) are derived from old classes. A huge body of knowledge has been built up around these classes over the years, yielding insights into relationships between chemical structure and biological properties. Such insights can guide the chemist to improve the clinical utility of novel members of the class and diminish the challenge of building drug-like properties (e.g. solubility and www.drugdiscoverytoday.com
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There are good arguments both ways here. Broad-spectrum agents can be used to treat patient symptoms before diagnostic results are available (Pro), but also compromise the host’s normal flora (Con). Narrow spectrum agents do not cause collateral damage to the normal flora (Pro), but multiple medications are required for broad cover (Con). For the purposes of this table, the term broad-spectrum means active against a range of Gram-positive species but does not exclude the possibility of Gram-negative activity as well. Narrow-spectrum means active against a single Gram-positive species or, in the case of attenuation of virulence, a limited range of species. b For a more detailed list of compounds, etc. in development refer to Supplementary Table 1.
a
Quorex (http://www.quorex.com/) No longer in this area Numerous other companies have looked Inhibitors of quorum sensing systems
(Development discontinued?)
Probably requires special diagnostics Could require concomitant use of antibacterial drugs Commensal friendly Attenuation of virulence
Narrow-spectrum
Daiichi (http://www.daiichi.com/) Efflux pump inhibitor (Gram-negative) for combination with quinolone. (Development discontinued?) Extend useful life of existing drugs Inhibition of resistance
Should reduce antibiotic use
Broad-spectrum
Not amenable to most drug classes Nothing since 1980s (b-lactamase inhibitors)
Nabi (http://www.nabi.com/) StaphVax (Phase 2: Launch 2005)
Antigenics (http://www.antigenics.com/) Quillimune-P (Phase 2: Launch 2006)
Replacement by non-vaccine serotypes Immunocompromised patients Early trials promising Vaccines
Narrow-spectrum
Daptomycin (Launched 2003) BB-83698 (Phase 1: Launch unknown) New technology Scaffolds often undruglike No resistance Registration might be easier
Broad-spectrum
Cons Pro and con?a
First-in-class
The tetracyclines have been compromised by widespread resistance, but two novel intravenous glycylcyclines, tigecy-
Numerous classes Much is known Drugable scaffold
Glycylcyclines (broad-spectrum, intravenous)
Best-in-class
The earlier quinolones had weak Gram-positive activity, but gatifloxacin (Bristol–Myers Squibb http://www.bms.com/) and moxifloxacin (Bayer http://www.bayer.com/) are two newer market entries that have largely addressed this issue. Garenoxacin (Toyama http://www.toyama-chemical.co.jp/ and Schering-Plough http://www.sch-plough.com/) and DX 619 (Daiichi Seiyaku http://www.daiichipharm.co.jp/) are two development quinolones, which appear to have extremely potent in vitro activity against Gram-positive organisms, including many which are resistant to other quinolones [10,11].
Pros
Quinolones (broad-spectrum, oral and intravenous)
Strategy
The market leaders in the class are the intravenous, hospital broad-spectrum agents ceftriaxone (no pseudomonas activity; dosed u.i.d) and ceftazidime (pseudomonas activity; dosed b.i.d). The major weakness of the class is a lack of activity against methicillin-resistant staphylococci (MRSA), and many of the cephalosporins currently in development claim utility against MRSA. Three intravenous and two oral cephalosporins are currently under development, focused mainly on hospital broad spectrum, most lacking pseudomonas activity.
Table 1. Comparison of the different Gram-positive treatment strategies
Cephalosporins (broad-spectrum, oral and intravenous)
Doripenem (Pre-reg: Launch 2004) Tigecycline (Phase 3: Launch 2004)
Latest developmentsb
The market leaders in this class are imipenem and meropenem, which are intravenous agents whose broad spectrum includes the Gram-negative organism Pseudomonas. A recent entry, ertapenem, is intravenous but lacks activity against Pseudomonas. R 115685 [8] (Roche; http://www.roche.com/ licensed from Sankyo; http://www.sankyo.co.jp/) and doripenem [9] (Shionogi; http://www.shionogi.co.jp/) are intravenous carbapenems aimed at the imipenem market. Peninsula (http:// www.peninsulapharm.com/) has in-licensed doripenem for some markets and is developing an inhaled formulation focused on cystic fibrosis. Tebipenem (Meiji-Seika; http:// www.meiji.co.jp/) is oral but lacks activityagainst Pseudomonas.
Resistance is widespread
Carbapenems (broad-spectrum, oral and intravenous)
Broad-spectrum
Who is working on this strategy?
bioavailability) into the molecule because they are already present in closely related existing drugs. On the downside, new compounds will be launched into an environment where widespread resistance already exists and cost-conscious healthcare policies often make it difficult to establish new agents in the market with only incremental improvements in potency, spectrum, pharmacokinetics or safety. Some of the major classes of novel agents currently in development are reviewed here and summarized in the Supplementary Table 1.
Cubist (http://www.cubist.com/) Oscient (http://www.oscient.com/)
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Shionogi (http://www.shionogi.co.jp/) Wyeth (http://www.wyeth.com/)
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cline [12,13] (Wyeth http://www.wyeth.com/) and PTK 0796 [14,15] (BAY-73-6944; Paratek http://www.paratekpharm.com/ licensed to Bayer) are not affected by the majority of these resistance mechanisms and have broad-spectrum activity, including activity against MRSA and VRE [15,16]. Ketolides (broad-spectrum, oral and intravenous)
Cethromycin (ABT-773) is a broad-spectrum, oral ketolide [17]. Abbott (http://www.abbott.com/) discontinued Phase 3 studies in 2002, although Taisho (http://www.taisho.co.jp/) have continued development in Japan. Several other companies (Chiron http://www.chiron.com/, Enanta http://www. enanta.com/, Pfizer http://www.pfizer.com/, Johnson & Johnson http://www.jnj.com/) are known to have ketolide programs at a pre-clinical stage.
First-in-class The easiest way to circumvent existing resistance mechanisms is to develop agents that inhibit novel targets, because it can generally be assumed that these will be launched into an environment lacking organisms with pre-existing targetbased resistance. In the past 15 years, rapid advances in genomics, genetics, chemistry, and automation have enabled the implementation of sophisticated, large-scale, target-based screens. The 1990s saw several companies rushing into genome-based, high-throughput antibacterial screening, and, for a variety of reasons, the 2000s have seen many of them rushing out again [18]! Although many of the essential single targets found in important clinical bacteria have been extensively screened, the current development pipeline contains few novel first-in-class compounds. So what has gone wrong? It is fair to say that the implementation path for this new screening paradigm has been littered with problems, many of which are only now reaching resolution (see Box 1 for examples of some of the chemistry-related issues). For a crucial review of the issues as they apply to modern drug research, refer to [19] and for an excellent infection-focused review, refer to [20]. Glycopeptide-like agents (Gram-positive only, intravenous only)
A class of bactericidal cell wall inhibitors, with vancomycin the market leader in the class, although vancomycin-resistance is now common among enterococci (VRE) and is appearing in staphylococci. Several compounds are in development or have recently been launched which are derived from natural products and act at targets close to that of vancomycin. All are intravenous, Gram-positive only agents. Last year saw the launch of daptomycin [21,22] (Cubist http://www.cubist.com/), a lipoglycopeptide that maintains activity against VRE. Four other glycopeptides or glycopeptide-like compounds are currently under development, most of which claim activity against VRE. Of these, dalbavancin
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Box 1. Struggling with compound diversity Many high-throughput screening campaigns result either in no hits worth pursuing or in highly lipophilic hits. Lipophilic molecules tend to be poorly soluble and highly serum bound, two features that need to be engineered out of the molecule to make it drug-like. Too often, however, biological activity is closely correlated with lipophilicity, so the more drug-like the molecule becomes, the less active it becomes. This is one of the principal reasons for the limited success seen so far in all therapy areas with target-based screening, and much thought has gone into what constitutes a good lead-generating library (see, e.g. Ref. [44]). Some would argue that this high failure rate reflects a lack of chemical diversity within compound collections. Expanding chemical diversity has been a high priority for pharmaceutical companies for several years and is still one the industry is struggling to address. With the advent of automation and miniaturization came combinatorial chemistry, which, for a while, promised a cost-effective way of building large, diversified compound libraries. So far, however, the promise remains largely unfulfilled [45]. There is also a drive for diversity through introducing large-scale natural product collections into compound banks [46] and some companies are once more trying to exploit natural products through the engineering of biosynthetic pathways (e.g. Kosan http://www.kosan.com/). It is certainly true that marketed antibacterials derived from natural products have a level of chemical complexity that is lacking from many compound collections and from marketed synthetic antibacterials [47].
[22,23] (Versicor http://www.vicuron.com/) has the distinction of once per week dosing, whereas oritavancin [13,22] (Intermune http://www.intermune.com/) and telavancin (Theravance http://www.theravance.com/) are dosed once daily. Ramoplanin [22] (Oscient http://www.oscient.com/) cannot be dosed intravenously and is under development for large bowel disinfection of Clostridium difficile and VRE. Recent intelligence suggests that development of oritavancin has terminated. Pepetide deformylase inhibitors (broad-spectrum, oral and intravenous)
These are the only truly novel agents known to be in development at present that are derived from genome-based target selection. Unfortunately, the high resistance rates observed in S. aureus and Escherichia coli are probable to limit the use of this series to community respiratory agents [22]. Oscient have taken one PDF inhibitor into man [24]; this compound lacked activity against Haemophilus influenzae, limiting its use as a respiratory antibacterial, but did show good human pharmacokinetics. Oscient are continuing to work on this series. Vicuron are also actively pursuing PDF inhibitors and one compound [25] has been licensed to Novartis (http:// www.novartis.com/) and is in Phase 1. Many other classes of compound derived from target-based screening are in late-stage discovery and have not yet moved into development. These include tRNA synthetase inhibitors [26,27] and inhibitors of fatty acid biosynthesis [28,29]. www.drugdiscoverytoday.com
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For a more comprehensive review of novel best-in-class and first-in-class Gram-positive agents in development, refer to the recent reviews [22,30,31].
Vaccines Vaccines have been used for the prevention of pneumococcal disease for almost a century but, until recently, have had limited success in those most at risk, the very young, the very old and the immunocompromised. Prevnar1 (Wyeth), the first protein-conjugated pneumococcal vaccine, was licensed in the USA in 2000 for routine use in children under two years old, and is the first to provide lasting protection to the very young [32]. In trials, it has shown a 93% reduction in invasive pneumococcal disease and a 73% reduction in consolidated pneumonia [33]. One interesting result of effective vaccination is indirect immunity or the herd ‘effect’, whereby pneumococcal infections in the unvaccinated are reduced owing to the presence of a vaccinated population [34]. Vaccination has significantly reduced the nasopharyngeal carriage of vaccine serotypes, but there is a simultaneous increase in the carriage rates of non-vaccine-serotypes [35]. This, plus the variation in serovars seen from country to country, has driven the development of vaccines of increasing valency, such as the 23-valent Quilimmune-P1 (Antigenics http://www.antigenic.com/). Undoubtedly, widespread use of these new S. pneumoniae vaccines, along with similarly effective vaccines against the Gram-negative pathogens H. influenzae and Neisseria meningitidis, should reduce the incidence of infection, and hence the use of antibacterials, in the young. A new entry in this area is StaphVAX1 (Nabi http:// www.nabi.com/), a vaccine directed at S. aureus capsular types 5 and 8, which together account for 80–90% of S. aureus clinical infections. The vaccine is in Phase III trials in kidney patients receiving peritoneal dialysis, a population at high risk from serious staphylococcal infection [36].
Inhibition of resistance mechanisms The strategy of partnering a b-lactam antibiotic with an agent that inhibits the more common b-lactam-inactivating enzymes has proven successful in the past, with AugmentinTM (GSK http://www.gsk.com/) and ZosynTM (Wyeth) the best commercial examples of the strategy. Despite a large effort in this area in the 1990s [37], no new combinations have appeared during the past 20 years, although there are a few novel b-lactamase inhibitors in pre-development [38]. Unfortunately, this approach seems unlikely to be successful for antibiotic classes other than b-lactams [39,40]. For many classes, resistance is mediated either by target mutation, target modification or altered metabolic pathway, where combination therapy is inappropriate and novel scaffolds with different target binding properties are the best way to address resistance. 458
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Enzymatic modification of the drug is another major mechanism of resistance and, for most drug classes, a wide range of enzymes are employed, necessitating a combination with multiple inhibitors and making both discovery and development high risk. The exception is the chloramphenicols, which are metabolized by a single class of enzymes [40]. Chloramphenicols have serious safety problems, however, and the higher regulatory hurdles in place today make it unlikely that a combination drug could be launched from this class. Many antibacterials are subject to efflux, and combining an antibiotic with an efflux pump inhibitor has been an elusive holy grail for some time [41]. Our understanding of these pumps is improving now that crystal structures are becoming available [42] but, so far, this strategy has not proved successful. An alternative strategy to inhibition of efflux pumps is the development of agents that are not subject to the efflux problems of earlier members of a series; an approach that has proved successful for tigecycline and PTK 0796 (mentioned above).
Attenuation of virulence Antibacterial agents arising from a first-in-class or best-inclass strategy cure by killing or inhibiting growth of the invading organism in the patient. A disadvantage of this method is the collateral death of many non-pathogenic organisms residing on and in the host, sometimes with unpleasant side effects (e.g. antibiotic-associated diarrhea).
Box 2. Some questions surrounding inhibition of virulence factors Many virulence factors are switched on in response to some signal from the host and are not present in cells growing on conventional laboratory media. This rules out standard in vitro testing, which makes the discovery process more arduous and means that a special diagnostic test must be launched simultaneously with any new drug, thus raising costs significantly. How will clinical laboratories assess susceptibility to these agents and, perhaps more importantly, the inevitable development of resistance to them? Most current animal models of infection utilize a lethal dose of infecting organism and look for rapid clearance of the infection. Colonization models, much less severe and much less reproducible, would be required for the evaluation of anti-virulence agents, and few exist at present. How can these models best be developed? Many infections require the pathogen to produce a variety of factors at different stages of the disease. Will the inhibition of a single factor be effective? How will such drugs be utilized; as prophylactics for high-risk patients, in combination with an antibacterial agent or as mono-therapy? How can these agents best be evaluated for registration?
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Bacteria produce virulence factors to enable host colonization and their inhibition could be considered a target for antimicrobial chemotherapy [43]. This type of chemical intervention would not be expected to have such a profound effect on the normal host flora because many virulence factors are found in a limited number of pathogens. But developing inhibitors of this type is no easy task. Although this strategy looks extremely promising at first sight, there remain many issues to address (see Box 2 for a partial list of unanswered questions) and there are signs that the initial enthusiasm for this approach is fading. As an example, Quorex (http:// www.quorex.com/), a company exclusively focused on this strategy from its inception, shifted to a first-in-class strategy in 2002.
isms. Within this strategy, the inhibition of bacterial broadspectrum efflux pumps probably has the greatest chance of success, but the complex structure and the multitude of binding sites in these pumps has so far defeated all comers. Meanwhile, antibiotic resistance continues to increase, sometimes at an alarming rate, and the race to keep up has been likened [22] to a quote from the Red Queen in Lewis Carroll’s book Alice Through The Looking Glass: ‘‘Now, here, you see, it takes all the running you can do, to keep in the same place.’’ Let us hope that we can slow the pace down using some of the strategies outlined here!
Conclusions
Supplementary data associated with this article can be found, in the online version, at 10.1016/j.ddstr.2004.08.015.
Three antibiotic classes, b-lactams, macrolides, and quinolones, have been the mainstays of infection therapy for the past 30 years or more and, judging from current development pipelines, look set to remain so for the immediate future. Unfortunately, the resistance mechanisms already present in community and hospital environments mean that most new compounds from these classes are likely to be compromised to some extent before they are even launched. The major exceptions could be the glycylcyclines (e.g. tigecycline), which seem to have overcome most of the major Grampositive tetracycline resistance mechanisms, and some of the glycopeptide-like agents (e.g. daptomycin), which inhibit targets close to that of vancomycin but maintain activity against vancomycin-resistant strains. The other strategies outlined in this review have not, so far, met with the same success as the best-in-class strategy. The plethora of novel antibacterial targets reported over the past 10 years have so far produced little to fill the antibiotic pipeline, although the recent Phase 1 trials of two peptide deformylase inhibitors might be the first signs that the genomically-driven, target-based screening approach is beginning to bear fruit. Let us hope that we see many more first-in-class agents in development in the near future. The new breed of protein-conjugated vaccines is already having an impact on respiratory infections in the young and might reduce the need for antibiotic intervention in this population. Whether they will be as successful in other indications and populations remains to be seen. No compound based on the strategy of inhibiting virulence factors has entered development as yet, and we must await the first of these to progress into human before we have answers to many of the fascinating questions posed by this approach. Finally, the inhibition of resistance mechanisms to existing antibiotic classes, which proved so successful for the penicillins, is unlikely to be a viable strategy for any other class due mainly to the multi-factorial nature of these mechan-
Appendix A. Supplementary data
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