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Resistance drives antibacterial drug development
Available online at www.sciencedirect.com
Resistance drives antibacterial drug development Ursula Theuretzbacher New resistance challenges continue to evolve and spread worldwide. In an otherwise mature field, antibacterial drug development is primarily driven by resistance trends with a focus on development of new analogs of known scaffolds to strengthen them against class-specific resistance mechanisms. Currently new analogs of cephalosporins (with or without beta-lactamase inhibitors), oxazolidinones, glycopeptides, quinolones, aminoglycosides, tetracyclines, and ketolides are in clinical studies. While showing some benefit, these new analogs only partially address the clinical crisis of multidrug-resistant pathogens; this is especially the case for Gram-negative bacteria. The medical community faces grim reality — general solutions to the treatment of rapidly spreading multidrug-resistant bacteria are neither on the horizon nor anticipated.
economic and medical justification for the development of new antibiotics that do not solve relevant resistance problems. Without resistance the future of antibacterial R&D would be limited [2].
Address Center for Anti-Infective Agents, Eckpergasse 13, 1180 Vienna, Austria
For the purpose of this article I define ‘new agents’ as a new chemical entity not related to a known antibacterial scaffold and not showing cross-resistance to existing drugs. Such a new antibacterial agent may present solutions to a range of clinical resistance challenges. At the same time, these novel compounds have two major resistance related problems of their own to overcome: rapid emergence of high-level resistance when targeting single enzymes (e.g. peptide deformylase inhibitors [5]) and nonselective efflux mechanisms. An excellent review on the challenges for research of novel antibiotics has been published recently [5]. As widely known, discovery of novel agents against new bacterial targets is regarded a risky business endeavor [6]. So, it is not surprising that the bulk of current antibacterial R&D activities [7] targets ‘lower risk’ strategies [8] built on alterations to existing classes of antibiotics (Figure 1). Indeed, most development activities are focused on expanding existing antibiotic classes targeted at the hospital sector [9].
Corresponding author: Theuretzbacher, Ursula ([email protected])
Current Opinion in Pharmacology 2011, 11:433–438 This review comes from a themed issue on Anti-infectives Edited by U. Theuretzbacher and J.W. Mouton Available online 19th August 2011 1471-4892/$ – see front matter # 2011 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2011.07.008
Introduction Bacteria demonstrate impressive effectiveness in adapting to changing environmental challenges. In contrast to most drugs in other medical fields, antibacterial drugs aim at shifting targets and, hence, lose their effectiveness over time. Because of lengthy research and development (R&D) time lines for new drugs, bacteria have outpaced our ability to react effectively to emerging resistance challenges. Antibiotics have a long history, beginning in the 1930s and earlier, during which several distinct drug classes were discovered and numerous improved analogs were made available [1]. Because of these efforts, today’s antibiotics satisfactorily address most clinical situations; the escalating multidrug resistance problem is a major exception. Therefore, resistance remains as a primary driver for antibacterial R&D. Indeed, there is little www.sciencedirect.com
This article examines major current antibacterial drug development activities. Using examples of improved analogs of known antibacterial classes for the hospital sector, the following sections explore the R&D response to the pressing worldwide resistance challenge and address the crucial question: Will the future antibacterial analogs be able to fill the gap of currently untreatable cases as described by Livermore et al. [3,4]?
Resistance drives antibacterial drug development
The rapid rise of methicillin-resistant Staphylococcus aureus (MRSA) [10] in the 1990s triggered a wave of activities in the Gram-positive area [9]. Inherent discovery challenges in the Gram-negative field coupled with commercial forces further amplified the focus on Gram-positives. Now, 10–20 years later, the fruits of this focus typify the predominantly Gram-positive products in antibacterial pipelines worldwide (Figure 2). The results of this Gram-positive focus have been heartening as the range of treatment options against MRSA and other Gram-positive bacteria has expanded over the recent years (linezolid, daptomycin, tigecycline, telavancin, ceftaroline). At the same time, glimpses of emerging resistance trends against these new drugs are already Current Opinion in Pharmacology 2011, 11:433–438
434 Anti-infectives
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Number (by April 2011) of i.v. antibacterial drugs (small molecules) in clinical development with focus on Gram-negative (excluding Pseudomonas only drugs, antibodies, vaccines) and Gram-positive bacteria. Drugs against new bacterial targets or new mode of action (new), analogs of known scaffolds (old).
apparent. And of growing clinical concern, in contrast to the progress against resistant Gram-positive bacteria, treatment options against Gram-negative bacteria, including pan-resistant enterobacteriaceae and nonfermenters are sparse at best [3,4,11,12,13].
New analogs of old classes to address hospital infections Exploration of structure–activity relationships using upto-date technology can lead to the rational preparation and evaluation of new analogs that offer some protection against one or more of the known resistance mechanisms. In particular, the process of adding chemical moieties that provide extra intramolecular-binding sites in order to overcome preexisting exogenous target-based resistance [5] has been applied in the development of several wellknown classes, such as cephalosporins active against MRSA, glycopeptides, tetracyclines, oxazolidinones, aminoglycosides, and ketolides (Figure 3).
Figure 2
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Current Opinion in Pharmacology
Number (by April 2011) of i.v. antibiotics (small and large molecules) in clinical development according to their focus of antibacterial activity. Clinical phase of development: Ph 1, Ph 2, and Ph 3. Current Opinion in Pharmacology 2011, 11:433–438
Clinically relevant resistance in staphylococci is based on the acquisition of the modified penicillin-binding-protein (PBP) 2a that mediates resistance to all long known betalactam antibiotics. In Gram-negative pathogens, the production of beta-lactamases, a major resistance mechanism in beta-lactam antibiotics, is increasingly associated with plasmid-encoded extended-spectrum beta-lactamases (ESBLs) and carbapenemases such as the KPC family and the VIM, IMP, and NDM metallo-enzymes [14,15]. These beta-lactamases are now appearing in multiple combinations of ESBLs and carbapenemases, thereby conferring resistance to virtually all beta-lactam antibiotics [16]. The acquisition of large mobile genetic elements encoding for multiple beta-lactamases and other resistance mechanisms enable rapid global dissemination of resistance [17] and calls into question the future of beta-lactam antibiotics [18]. In nonfermenters (Pseudomonas and Acinetobacter) efflux and penetration barriers, and sometimes PBP changes become significant [19]. Resistance to multiple drugs is usually the result of the www.sciencedirect.com
Resistance drives antibacterial drug development Theuretzbacher 435
combination of different mechanisms within a single isolate [20]. Cephalosporins
In response to the emerging MRSA threat, the existing cephalosporin scaffold was re-explored to improve the binding to PBP2a. The results of the optimization processes are the two recent cephalosporins with MRSA activity: ceftaroline and ceftobiprole [21]. Ceftobiprole was rejected by the US and EU regulatory authorities because of irregularities and data integrity issues in phase 3 trials. However, ceftaroline has been recently approved for acute bacterial skin and soft tissue infections (ABSSI) and moderate to severe community-acquired pneumonia (CAP) [22]. Ceftaroline’s Gram-negative activity is comparable to cefotaxime and thus, hampered by hydrolysis by ESBLs, AmpC-beta-lactamases, and most carbapenemases [23]. Beta-lactamase inhibitor combinations
Old and recently developed cephalosporins are threatened by ever evolving new beta-lactamases [24]. To rescue or at least improve the activity of cephalosporins, the well-known and established practice of using betalactamase inhibitor combinations has been revived and applied to recent developmental activities. The available inhibitors clavulanic acid, sulbactam, and tazobactam show effectiveness primarily against class A beta-lactamases (conventional TEM/SHV, most ESBLs); indeed, these were the predominant and clinically relevant enzymes when beta-lactamase inhibitors were first developed about 30 years ago. The new cephalosporin analog CXA-101 has improved activity against Pseudomonas aeruginosa but is hydrolyzed by relevant beta-lactamases. Therefore, it will be combined with tazobactam (CXA-101 + tazobactam = CXA-201, phase 3 for complicated urinary tract infections, cUTI) to overcome some of the beta-lactamase mediated resistance challenges. This is a good example of a drug development activity that fixes some resistance problems but still does not address recent essential resistance trends [25]. Several new beta-lactamase inhibitors are currently in clinical development in combination with both old and new cephalosporins. The non-beta-lactam inhibitor avibactam (NXL-104), with expanded inhibitory activity against ESBLs, AmpC-beta-lactamases, class A carbapenemases (KPC), and some OXA-producing strains (OXA48), is showing promise in studies in combination with ceftazidime (CAZ-104, phase 2) [26] as well as ceftaroline for cUTI caused by enterobacteriaceae. Against Pseudomonas the effect of the combinations is less pronounced [27] as nonenzymatic resistance mechanisms prevail. The new inhibitor of class A, C, and D beta-lactamases BLI-489 was combined with piperacillin [27]. MK7655, an inhibitor of class A and C beta-lactamases, is studied in www.sciencedirect.com
combination with imipenem [12]. It is unclear if these combinations will be developed further. Similarly, several other new beta-lactamase inhibitors in preclinical development are most likely not pursued. There is no doubt that the adaptability and complexity of beta-lactamases will continue to surprise us and even highly improved beta-lactamase inhibitors may be only partially protective as a combination of several betalactamases or hyperproduction may simply overwhelm any inhibitor [26]. Monobactams
Currently, one new analog of the monobactam class is in early clinical development. Similar to aztreonam, BAL30072, a siderophore monosulfactam, is a poor substrate for class B metallo-beta-lactamases and acts as a mechanism-based inhibitor of class C beta-lactamases [28]. BAL30072 has its merits especially against MDR Acinetobacter baumannii (harboring AmpC and OXA betalactamases) [29], Burkholderia cepacia complex, Stenotrophomonas maltophilia and to some extent P. aeruginosa [30]. Already existing or future resistance threats for this new monobactam include hyperproduction of beta-lactamases as well as efflux upregulation of MexAB-OprM and MexEF-OprN in Pseudomonas [28]. It is not yet known if resistance due to inactivation of tonB with the resulting loss of the iron transport system through the bacterial outer membrane will arise in vivo [31]. Aminoglycosides
There have been several attempts to modify the aminoglycoside scaffold to overcome the most common aminoglycoside-modifying enzymes (AMEs). ACHN490, a semisynthetic molecule derived from sisomicin, is in phase 2 clinical testing for cUTI. The compound has similar activity to gentamicin in enterobacteriaceae or to amikacin in Pseudomonas and Acinetobacter against wild-type strains [32]. ACHN-490 retains activity against the most common AMEs [33]. Against clinical strains of MDR A. baumanii and P. aeruginosa the MICs are elevated [34] as well as too high against MDR Klebsiella with ArmA methylases [35]. As the protection against the specific aminoglycoside resistance mechanisms is not complete, the increasing prevalence of strains harboring multiple and still uncommon AMEs coupled with panaminoglycoside-exporting efflux systems threatens to compromise the use of this entire class in the long run [36]. Quinolones
The medical need is apparent: quinolone-resistant enterobacteriaceae are rapidly spreading in hospitals and the community. Resistance trends in Gram-negative bacteria are outpacing industry R&D decision making as optimization efforts, which have been focused on Gram-positive bacteria, have been slow to change. Current Opinion in Pharmacology 2011, 11:433–438
436 Anti-infectives
Several quinolone analogs with enhanced activity against Gram-positive cocci have advanced to the clinical development stage but the new analogs do not address the most pressing medical problem of ciprofloxacin-resistant enterobacteriaceae. Delafloxacin and JNJ-Q2 (=JNJ32729463), both with improved activity against quinolone-resistant Gram-positive bacteria overcome first step mutations and have been tested in ABSSI and CAP. Nemonoxacin, a nonfluorinated quinolone, and WCK 771, the active isomer of nadifloxacin, do not solve any quinolone-specific resistance problem [37,38] and their potential clinical usefulness is unclear. Glycopeptides
The continued spread of MRSA and the appearance of high-level resistance to vancomycin has spurred interest in this antibacterial class [39]. Semisynthetic analogs based on traditional glycopeptide scaffolds were synthesized with modified side chains to improve the activity against vancomycin-resistant strains. Oritavancin, dalbavancin, and telavancin were developed and telavancin recently achieved approval while oritavancin and dalbavancin are back to the starting line with late clinical development programs. While vancomycin resistance in MRSA is not common today, it will certainly increase in the future; hence, the impact of the new glycopeptides on solving future resistance problems of this class could be crucial but are uncertain. Oxazolidinones
The most advanced novel analogs of the oxazolidinone class, torezolid and radezolid, have demonstrated improved affinity for the ribosomal target compared to linezolid [40–42]. The new compounds show some crossresistance with linezolid demonstrated by twofold to threefold MIC increases in S. aureus strains with mutations in 23S rRNA or ribosomal proteins L3 and L4 [40,42,43]. Because of their higher intrinsic activity and thus lower MIC50 values in the wild-type strains, the MIC shift may still be in the susceptible range provided an adequate dosage regime is selected to include such strains [44].
proteins and minimally or unaffected by the most common tetracycline efflux pumps. Macrolides/ketolides
Similar to the ketolides telithromycin and cethromycin, solithromycin shows improved binding to the ribosomal target and is active against multidrug-resistant community-acquired pneumococci [45]. Solithromycin is undergoing phase 2 clinical trials in CAP patients.
Conclusion Resistance is the primary driver of new antibacterial drug development activities. Again and again, the complexity and diversity of resistance mechanisms defies anticipation as synergistic combinations of known and new resistance mechanisms drive emergence of multiresistant phenotypes. Yet, R&D’s primary focus remains on the development of new analogs of well-known scaffolds, trying to face the ever evolving complexities of resistance. Still, depending on the modified antibacterial class, these analogs may be partially effective and, for a few years, are likely to provide additional antibiotics that are effective against specific resistant strains. Consider, however, that cross-resistance is already apparent or anticipated against every one of the new analogs currently in the development pipeline. In general, these modification strategies will become less and less productive as avoidance of even the already recognized resistance factors is not feasible. While the race between drug development and emergence of resistance continues, the medical community must face the situation — general solutions to the treatment of rapidly spreading multidrug-resistant bacteria are neither on the horizon nor anticipated. Given the absence of other tools, resistance challenges will compel clinicians to employ few newly available analogs of known antibiotic classes with targeted activity. Ways forward include the efficient integration of rapid diagnostic tools into the disease management strategy, infection control, and professional stewardship programs.
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as:
Tetracyclines
Two new tetracycline derivates are in clinical development. Omadacycline, in phase 3 clinical trials for the treatment of ABSSI, has an improved affinity for ribosome-binding sites and thus, partially addresses tetracycline resistance. The MICs against Gram-positive bacteria are comparable to tigecycline or one dilution step higher. TP-434 is in phase II clinical development for complicated intraabdominal infections. It has a spectrum comparable to minocycline with some improvements in the activity against Proteus and Acinetobacter but without activity against Pseudomonas. TP-434 and other new analogs are unaffected by ribosomal protection Current Opinion in Pharmacology 2011, 11:433–438
of special interest of outstanding interest 1.
Bush K: The coming of age of antibiotics: discovery and therapeutic value. Ann N Y Acad Sci 2010, 1213:1-4.
2.
Hughes JM: Preserving the lifesaving power of antimicrobial agents. JAMA 2011 doi: 10.1001/jama.2011.1279.
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Livermore DM, Warner M, Mushtaq S, Doumith M, Zhang J, Woodford N: What remains against carbapenem-resistant Enterobacteriaceae? Evaluation of chloramphenicol, ciprofloxacin, colistin, fosfomycin, minocycline, nitrofurantoin, temocillin and tigecycline. Int J Antimicrob Agents 2011, 37:415-419.
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Resistance drives antibacterial drug development Theuretzbacher 437
5. Silver LL: Challenges of antibacterial discovery. Clin Microbiol Rev 2011, 24:71-109. This recent review elucidates the scientific challenges to the discovery of novel small-molecule antibacterials and the rate-limiting steps to the discovery process.
24. Bush K: Bench-to-bedside review: the role of beta-lactamases in antibiotic-resistant Gram-negative infections. Crit Care 2010, 14:224.
Warren J: Drug discovery: lessons from evolution. Br J Clin Pharmacol 2011, 71:497-503.
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7. Moellering RC Jr: Discovering new antimicrobial agents. Int J Antimicrob Agents 2011, 37:2-9. Describing antimicrobial R&D activities, the author documents other antimicrobial approaches including potentiators, hybrids, virulence inhibitors and agents against new targets.
26. Livermore DM, Mushtaq S, Warner M, Zhang J, Maharjan S, Doumith M, Woodford N: Activities of NXL104 combinations with ceftazidime and aztreonam against carbapenemaseproducing Enterobacteriaceae. Antimicrob Agents Chemother 2011, 55:390-394.
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27. Drawz SM, Bonomo RA: Three decades of beta-lactamase inhibitors. Clin Microbiol Rev 2010, 23:160-201. For those who are interested in the challenges of beta-lactamase inhibitor development as well as inhibitor-resistant enzymes!
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10. Chambers HF, Deleo FR: Waves of resistance: Staphylococcus aureus in the antibiotic era. Nat Rev Microbiol 2009, 7:629-641. 11. van der Donk CFM, Beisser PS, Hoogkamp-Korstanje JAA, Bruggeman CA, Stobberingh EE: A 12 year (1998–2009) antibiotic resistance surveillance of Klebsiella pneumoniae collected from intensive care and urology patients in 14 Dutch hospitals. J Antimicrob Chemother 2011, 66:855-858. 12. Coates ARM, Halls G, Hu Y: Novel classes of antibiotics or more of the same? Br J Clin Pharmacol 2011, 163:184-194. 13. Alvan G, Edlund C, Heddini A: The global need for effective antibiotics — a summary of plenary presentations. Drug Resist Updat 2011, 14:70-76. The authors highlight the global need for effective antibiotics and explore possible concerted actions for change. 14. Bush K, Jacoby GA: An updated functional classification of betalactamases. Antimicrob Agents Chemother 2010, 54:969-976. 15. Cornaglia G, Giamarellou H, Rossolini GM: Metallo-betalactamases: a last frontier for beta-lactams? Lancet Infect Dis 2011, 11:381-393. 16. Bush K: Alarming beta-lactamase-mediated resistance in multidrug-resistant Enterobacteriaceae. Curr Opin Microbiol 2010, 13:558-564. The author explains how beta-lactamases appear in multiple combinations, spread via mobile elements and are transferred worldwide. 17. Van der Bij AK, Van Mansfeld R, Peirano G, Goessens WHF, Severin JA, Pitout JDD, Willems R, Van Westreenen M: First outbreak of VIM-2 metallo-beta-lactamase-producing Pseudomonas aeruginosa in The Netherlands: microbiology, epidemiology and clinical outcomes. Int J Antimicrob Agents 2011 doi: 10.1016/j.ijantimicag.2011.1002.1010. 18. Llarrull LI, Testero SA, Fisher JF, Mobashery S: The future of the [beta]-lactams. Curr Opin Microbiol 2010, 13:551-557. 19. Cabot G, Ocampo-Sosa AA, Tubau F, Macia MD, Rodriguez C, Moya B, Zamorano L, Suarez C, Pena C, Martinez-Martinez L et al.: Overexpression of AmpC and efflux pumps in Pseudomonas aeruginosa isolates from bloodstream infections: prevalence and impact on resistance in a Spanish Multicenter Study. Antimicrob Agents Chemother 2011, 55:1906-1911. 20. Zavascki AP, Carvalhaes CLG, Pica˜o RC, Gales AC: Multidrug resistant Pseudomonas aeruginosa and Acinetobacter baumannii: resistance mechanisms and implications for therapy. Expert Rev Anti Infect Ther 2010, 8:71-93. Excellent review on the resistance challenges of the nonfermenters Pseudomonas and Acinetobacter. 21. Livermore DM: Can b-lactams be re-engineered to beat MRSA? Clin Microbiol Infect 2006, 12:11-16. 22. Saravolatz LD, Stein GE, Johnson LB: Ceftaroline: a novel cephalosporin with activity against methicillin-resistant Staphylococcus aureus. Clin Infect Dis 2011, 52:1156-1163. 23. Mushtaq S, Warner M, Ge Y, Kaniga K, Livermore DM: In vitro activity of ceftaroline (PPI-0903M, T-91825) against bacteria with defined resistance mechanisms and phenotypes. J Antimicrob Chemother 2007, 60:300-311. www.sciencedirect.com
28. Page MGP, Dantier C, Desarbre E: In vitro properties of BAL30072, a novel siderophore sulfactam with activity against multiresistant Gram-negative bacilli. Antimicrob Agents Chemother 2010, 54:2291-2302. 29. Russo TA, Page MGP, Beanan JM, Olson R, Hujer AM, Hujer KM, Jacobs M, Bajaksouzian S, Endimiani A, Bonomo RA: In vivo and in vitro activity of the siderophore monosulfactam BAL30072 against Acinetobacter baumannii. J Antimicrob Chemother 2011, 66:867-873. 30. Mushtaq S, Warner M, Livermore D: Activity of the siderophore monobactam BAL30072 against multiresistant nonfermenters. J Antimicrob Chemother 2010, 65:266-270. 31. Martinez JL, Baquero F: Interactions among strategies associated with bacterial infection: pathogenicity, epidemicity, and antibiotic resistance. Clin Microbiol Rev 2002, 15:647-679. 32. Armstrong ES, Miller GH: Combating evolution with intelligent design: the neoglycoside ACHN-490. Curr Opin Microbiol 2010, 13:565-573. 33. Aggen JB, Armstrong ES, Goldblum AA, Dozzo P, Linsell MS, Gliedt MJ, Hildebrandt DJ, Feeney LA, Kubo A, Matias RD et al.: Synthesis and spectrum of the neoglycoside ACHN-490. Antimicrob Agents Chemother 2010, 54:4636-4642. 34. Landman D, Kelly P, Ba¨cker M, Babu E, Shah N, Bratu S, Quale J: Antimicrobial activity of a novel aminoglycoside, ACHN-490, against Acinetobacter baumannii and Pseudomonas aeruginosa from New York City. J Antimicrob Chemother 2010, 66:332-334. 35. Livermore DM, Mushtaq S, Warner M, Zhang JC, Maharjan S, Doumith M, Woodford N: Activity of aminoglycosides, including ACHN-490, against carbapenem-resistant Enterobacteriaceae isolates. J Antimicrob Chemother 2011, 66:48-53. 36. Poole K: Aminoglycoside resistance in Pseudomonas aeruginosa. Antimicrob Agents Chemother 2005, 49:479-487. 37. Lauderdale T-L, Shiau Y-R, Lai J-F, Chen H-C, King C-HR: Comparative in vitro activities of nemonoxacin (TG-873870), a novel nonfluorinated quinolone, and other quinolones against clinical isolates. Antimicrob Agents Chemother 2010, 54:1338-1342. 38. Bhagwat SS, McGhee P, Kosowska-Shick K, Patel MV, Appelbaum PC: In vitro activity of the quinolone WCK 771 against recent U.S. hospital and community-acquired Staphylococcus aureus pathogens with various resistance types. Antimicrob Agents Chemother 2009, 53:811-813. 39. Allen NE: From vancomycin to oritavancin: the discovery and development of a novel lipoglycopeptide antibiotic. Anti Infect Agents Med Chem 2010, 9:23-47. 40. Skripkin E, McConnell TS, DeVito J, Lawrence L, Ippolito JA, Duffy EM, Sutcliffe J, Franceschi F: Rx-01, a new family of oxazolidinones that overcome ribosome-based linezolid resistance. Antimicrob Agents Chemother 2008, 52:3550-3557. 41. Im WB, Choi SH, Park J-Y, Choi SH, Finn J, Yoon S-H: Discovery of torezolid as a novel 5-hydroxymethyl-oxazolidinone antibacterial agent. Eur J Med Chem 2011, 46:1027-1039. Current Opinion in Pharmacology 2011, 11:433–438
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42. Lawrence L, Danese P, DeVito J, Franceschi F, Sutcliffe J: In vitro activities of the Rx-01 oxazolidinones against hospital and community pathogens. Antimicrob Agents Chemother 2008, 52:1653-1662. 43. Locke JB, Finn J, Hilgers M, Morales G, Rahawi S, C.K. G, Picazo JJ, Im W, Shaw KJ, Stein JL: Structure–activity relationships of diverse oxazolidinones for linezolid-resistant Staphylococcus aureus strains possessing the cfr methyltransferase gene or ribosomal mutations. Antimicrob Agents Chemother 2010, 54:5337-5343.
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44. Prokocimer P, Bien P, Surber J, Mehra P, DeAnda C, Bulitta JB, Corey GR: Phase 2, randomized, double-blind, dose-ranging study evaluating the safety, tolerability, population pharmacokinetics, and efficacy of oral torezolid phosphate in patients with complicated skin and skin structure infections. Antimicrob Agents Chemother 2011, 55:583-592. 45. Llano-Sotelo B, Dunkle J, Klepacki D, Zhang W, Fernandes P, Cate JHD, Mankin AS: Binding and action of CEM-101, a new fluoroketolide antibiotic that inhibits protein synthesis. Antimicrob Agents Chemother 2010, 54:4961-4970.
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Resistance drives antibacterial drug development Ursula Theuretzbacher New resistance challenges continue to evolve and spread worldwide. In an otherwise mature field, antibacterial drug development is primarily driven by resistance trends with a focus on development of new analogs of known scaffolds to strengthen them against class-specific resistance mechanisms. Currently new analogs of cephalosporins (with or without beta-lactamase inhibitors), oxazolidinones, glycopeptides, quinolones, aminoglycosides, tetracyclines, and ketolides are in clinical studies. While showing some benefit, these new analogs only partially address the clinical crisis of multidrug-resistant pathogens; this is especially the case for Gram-negative bacteria. The medical community faces grim reality — general solutions to the treatment of rapidly spreading multidrug-resistant bacteria are neither on the horizon nor anticipated.
economic and medical justification for the development of new antibiotics that do not solve relevant resistance problems. Without resistance the future of antibacterial R&D would be limited [2].
Address Center for Anti-Infective Agents, Eckpergasse 13, 1180 Vienna, Austria
For the purpose of this article I define ‘new agents’ as a new chemical entity not related to a known antibacterial scaffold and not showing cross-resistance to existing drugs. Such a new antibacterial agent may present solutions to a range of clinical resistance challenges. At the same time, these novel compounds have two major resistance related problems of their own to overcome: rapid emergence of high-level resistance when targeting single enzymes (e.g. peptide deformylase inhibitors [5]) and nonselective efflux mechanisms. An excellent review on the challenges for research of novel antibiotics has been published recently [5]. As widely known, discovery of novel agents against new bacterial targets is regarded a risky business endeavor [6]. So, it is not surprising that the bulk of current antibacterial R&D activities [7] targets ‘lower risk’ strategies [8] built on alterations to existing classes of antibiotics (Figure 1). Indeed, most development activities are focused on expanding existing antibiotic classes targeted at the hospital sector [9].
Corresponding author: Theuretzbacher, Ursula ([email protected])
Current Opinion in Pharmacology 2011, 11:433–438 This review comes from a themed issue on Anti-infectives Edited by U. Theuretzbacher and J.W. Mouton Available online 19th August 2011 1471-4892/$ – see front matter # 2011 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2011.07.008
Introduction Bacteria demonstrate impressive effectiveness in adapting to changing environmental challenges. In contrast to most drugs in other medical fields, antibacterial drugs aim at shifting targets and, hence, lose their effectiveness over time. Because of lengthy research and development (R&D) time lines for new drugs, bacteria have outpaced our ability to react effectively to emerging resistance challenges. Antibiotics have a long history, beginning in the 1930s and earlier, during which several distinct drug classes were discovered and numerous improved analogs were made available [1]. Because of these efforts, today’s antibiotics satisfactorily address most clinical situations; the escalating multidrug resistance problem is a major exception. Therefore, resistance remains as a primary driver for antibacterial R&D. Indeed, there is little www.sciencedirect.com
This article examines major current antibacterial drug development activities. Using examples of improved analogs of known antibacterial classes for the hospital sector, the following sections explore the R&D response to the pressing worldwide resistance challenge and address the crucial question: Will the future antibacterial analogs be able to fill the gap of currently untreatable cases as described by Livermore et al. [3,4]?
Resistance drives antibacterial drug development
The rapid rise of methicillin-resistant Staphylococcus aureus (MRSA) [10] in the 1990s triggered a wave of activities in the Gram-positive area [9]. Inherent discovery challenges in the Gram-negative field coupled with commercial forces further amplified the focus on Gram-positives. Now, 10–20 years later, the fruits of this focus typify the predominantly Gram-positive products in antibacterial pipelines worldwide (Figure 2). The results of this Gram-positive focus have been heartening as the range of treatment options against MRSA and other Gram-positive bacteria has expanded over the recent years (linezolid, daptomycin, tigecycline, telavancin, ceftaroline). At the same time, glimpses of emerging resistance trends against these new drugs are already Current Opinion in Pharmacology 2011, 11:433–438
434 Anti-infectives
Figure 1
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Number of new analogs (by April 2011) in known classes according to their clinical development phase. BLI: beta-lactamase inhibitor.
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Number (by April 2011) of i.v. antibacterial drugs (small molecules) in clinical development with focus on Gram-negative (excluding Pseudomonas only drugs, antibodies, vaccines) and Gram-positive bacteria. Drugs against new bacterial targets or new mode of action (new), analogs of known scaffolds (old).
apparent. And of growing clinical concern, in contrast to the progress against resistant Gram-positive bacteria, treatment options against Gram-negative bacteria, including pan-resistant enterobacteriaceae and nonfermenters are sparse at best [3,4,11,12,13].
New analogs of old classes to address hospital infections Exploration of structure–activity relationships using upto-date technology can lead to the rational preparation and evaluation of new analogs that offer some protection against one or more of the known resistance mechanisms. In particular, the process of adding chemical moieties that provide extra intramolecular-binding sites in order to overcome preexisting exogenous target-based resistance [5] has been applied in the development of several wellknown classes, such as cephalosporins active against MRSA, glycopeptides, tetracyclines, oxazolidinones, aminoglycosides, and ketolides (Figure 3).
Figure 2
Beta-lactam antibiotics 20 18
Ph 3
16
Ph 2
14
Ph 1
12 10 8 6 4 2 0 Grampositive
Staphyloc. only
Gramnegative
Pseudom. only
Current Opinion in Pharmacology
Number (by April 2011) of i.v. antibiotics (small and large molecules) in clinical development according to their focus of antibacterial activity. Clinical phase of development: Ph 1, Ph 2, and Ph 3. Current Opinion in Pharmacology 2011, 11:433–438
Clinically relevant resistance in staphylococci is based on the acquisition of the modified penicillin-binding-protein (PBP) 2a that mediates resistance to all long known betalactam antibiotics. In Gram-negative pathogens, the production of beta-lactamases, a major resistance mechanism in beta-lactam antibiotics, is increasingly associated with plasmid-encoded extended-spectrum beta-lactamases (ESBLs) and carbapenemases such as the KPC family and the VIM, IMP, and NDM metallo-enzymes [14,15]. These beta-lactamases are now appearing in multiple combinations of ESBLs and carbapenemases, thereby conferring resistance to virtually all beta-lactam antibiotics [16]. The acquisition of large mobile genetic elements encoding for multiple beta-lactamases and other resistance mechanisms enable rapid global dissemination of resistance [17] and calls into question the future of beta-lactam antibiotics [18]. In nonfermenters (Pseudomonas and Acinetobacter) efflux and penetration barriers, and sometimes PBP changes become significant [19]. Resistance to multiple drugs is usually the result of the www.sciencedirect.com
Resistance drives antibacterial drug development Theuretzbacher 435
combination of different mechanisms within a single isolate [20]. Cephalosporins
In response to the emerging MRSA threat, the existing cephalosporin scaffold was re-explored to improve the binding to PBP2a. The results of the optimization processes are the two recent cephalosporins with MRSA activity: ceftaroline and ceftobiprole [21]. Ceftobiprole was rejected by the US and EU regulatory authorities because of irregularities and data integrity issues in phase 3 trials. However, ceftaroline has been recently approved for acute bacterial skin and soft tissue infections (ABSSI) and moderate to severe community-acquired pneumonia (CAP) [22]. Ceftaroline’s Gram-negative activity is comparable to cefotaxime and thus, hampered by hydrolysis by ESBLs, AmpC-beta-lactamases, and most carbapenemases [23]. Beta-lactamase inhibitor combinations
Old and recently developed cephalosporins are threatened by ever evolving new beta-lactamases [24]. To rescue or at least improve the activity of cephalosporins, the well-known and established practice of using betalactamase inhibitor combinations has been revived and applied to recent developmental activities. The available inhibitors clavulanic acid, sulbactam, and tazobactam show effectiveness primarily against class A beta-lactamases (conventional TEM/SHV, most ESBLs); indeed, these were the predominant and clinically relevant enzymes when beta-lactamase inhibitors were first developed about 30 years ago. The new cephalosporin analog CXA-101 has improved activity against Pseudomonas aeruginosa but is hydrolyzed by relevant beta-lactamases. Therefore, it will be combined with tazobactam (CXA-101 + tazobactam = CXA-201, phase 3 for complicated urinary tract infections, cUTI) to overcome some of the beta-lactamase mediated resistance challenges. This is a good example of a drug development activity that fixes some resistance problems but still does not address recent essential resistance trends [25]. Several new beta-lactamase inhibitors are currently in clinical development in combination with both old and new cephalosporins. The non-beta-lactam inhibitor avibactam (NXL-104), with expanded inhibitory activity against ESBLs, AmpC-beta-lactamases, class A carbapenemases (KPC), and some OXA-producing strains (OXA48), is showing promise in studies in combination with ceftazidime (CAZ-104, phase 2) [26] as well as ceftaroline for cUTI caused by enterobacteriaceae. Against Pseudomonas the effect of the combinations is less pronounced [27] as nonenzymatic resistance mechanisms prevail. The new inhibitor of class A, C, and D beta-lactamases BLI-489 was combined with piperacillin [27]. MK7655, an inhibitor of class A and C beta-lactamases, is studied in www.sciencedirect.com
combination with imipenem [12]. It is unclear if these combinations will be developed further. Similarly, several other new beta-lactamase inhibitors in preclinical development are most likely not pursued. There is no doubt that the adaptability and complexity of beta-lactamases will continue to surprise us and even highly improved beta-lactamase inhibitors may be only partially protective as a combination of several betalactamases or hyperproduction may simply overwhelm any inhibitor [26]. Monobactams
Currently, one new analog of the monobactam class is in early clinical development. Similar to aztreonam, BAL30072, a siderophore monosulfactam, is a poor substrate for class B metallo-beta-lactamases and acts as a mechanism-based inhibitor of class C beta-lactamases [28]. BAL30072 has its merits especially against MDR Acinetobacter baumannii (harboring AmpC and OXA betalactamases) [29], Burkholderia cepacia complex, Stenotrophomonas maltophilia and to some extent P. aeruginosa [30]. Already existing or future resistance threats for this new monobactam include hyperproduction of beta-lactamases as well as efflux upregulation of MexAB-OprM and MexEF-OprN in Pseudomonas [28]. It is not yet known if resistance due to inactivation of tonB with the resulting loss of the iron transport system through the bacterial outer membrane will arise in vivo [31]. Aminoglycosides
There have been several attempts to modify the aminoglycoside scaffold to overcome the most common aminoglycoside-modifying enzymes (AMEs). ACHN490, a semisynthetic molecule derived from sisomicin, is in phase 2 clinical testing for cUTI. The compound has similar activity to gentamicin in enterobacteriaceae or to amikacin in Pseudomonas and Acinetobacter against wild-type strains [32]. ACHN-490 retains activity against the most common AMEs [33]. Against clinical strains of MDR A. baumanii and P. aeruginosa the MICs are elevated [34] as well as too high against MDR Klebsiella with ArmA methylases [35]. As the protection against the specific aminoglycoside resistance mechanisms is not complete, the increasing prevalence of strains harboring multiple and still uncommon AMEs coupled with panaminoglycoside-exporting efflux systems threatens to compromise the use of this entire class in the long run [36]. Quinolones
The medical need is apparent: quinolone-resistant enterobacteriaceae are rapidly spreading in hospitals and the community. Resistance trends in Gram-negative bacteria are outpacing industry R&D decision making as optimization efforts, which have been focused on Gram-positive bacteria, have been slow to change. Current Opinion in Pharmacology 2011, 11:433–438
436 Anti-infectives
Several quinolone analogs with enhanced activity against Gram-positive cocci have advanced to the clinical development stage but the new analogs do not address the most pressing medical problem of ciprofloxacin-resistant enterobacteriaceae. Delafloxacin and JNJ-Q2 (=JNJ32729463), both with improved activity against quinolone-resistant Gram-positive bacteria overcome first step mutations and have been tested in ABSSI and CAP. Nemonoxacin, a nonfluorinated quinolone, and WCK 771, the active isomer of nadifloxacin, do not solve any quinolone-specific resistance problem [37,38] and their potential clinical usefulness is unclear. Glycopeptides
The continued spread of MRSA and the appearance of high-level resistance to vancomycin has spurred interest in this antibacterial class [39]. Semisynthetic analogs based on traditional glycopeptide scaffolds were synthesized with modified side chains to improve the activity against vancomycin-resistant strains. Oritavancin, dalbavancin, and telavancin were developed and telavancin recently achieved approval while oritavancin and dalbavancin are back to the starting line with late clinical development programs. While vancomycin resistance in MRSA is not common today, it will certainly increase in the future; hence, the impact of the new glycopeptides on solving future resistance problems of this class could be crucial but are uncertain. Oxazolidinones
The most advanced novel analogs of the oxazolidinone class, torezolid and radezolid, have demonstrated improved affinity for the ribosomal target compared to linezolid [40–42]. The new compounds show some crossresistance with linezolid demonstrated by twofold to threefold MIC increases in S. aureus strains with mutations in 23S rRNA or ribosomal proteins L3 and L4 [40,42,43]. Because of their higher intrinsic activity and thus lower MIC50 values in the wild-type strains, the MIC shift may still be in the susceptible range provided an adequate dosage regime is selected to include such strains [44].
proteins and minimally or unaffected by the most common tetracycline efflux pumps. Macrolides/ketolides
Similar to the ketolides telithromycin and cethromycin, solithromycin shows improved binding to the ribosomal target and is active against multidrug-resistant community-acquired pneumococci [45]. Solithromycin is undergoing phase 2 clinical trials in CAP patients.
Conclusion Resistance is the primary driver of new antibacterial drug development activities. Again and again, the complexity and diversity of resistance mechanisms defies anticipation as synergistic combinations of known and new resistance mechanisms drive emergence of multiresistant phenotypes. Yet, R&D’s primary focus remains on the development of new analogs of well-known scaffolds, trying to face the ever evolving complexities of resistance. Still, depending on the modified antibacterial class, these analogs may be partially effective and, for a few years, are likely to provide additional antibiotics that are effective against specific resistant strains. Consider, however, that cross-resistance is already apparent or anticipated against every one of the new analogs currently in the development pipeline. In general, these modification strategies will become less and less productive as avoidance of even the already recognized resistance factors is not feasible. While the race between drug development and emergence of resistance continues, the medical community must face the situation — general solutions to the treatment of rapidly spreading multidrug-resistant bacteria are neither on the horizon nor anticipated. Given the absence of other tools, resistance challenges will compel clinicians to employ few newly available analogs of known antibiotic classes with targeted activity. Ways forward include the efficient integration of rapid diagnostic tools into the disease management strategy, infection control, and professional stewardship programs.
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as:
Tetracyclines
Two new tetracycline derivates are in clinical development. Omadacycline, in phase 3 clinical trials for the treatment of ABSSI, has an improved affinity for ribosome-binding sites and thus, partially addresses tetracycline resistance. The MICs against Gram-positive bacteria are comparable to tigecycline or one dilution step higher. TP-434 is in phase II clinical development for complicated intraabdominal infections. It has a spectrum comparable to minocycline with some improvements in the activity against Proteus and Acinetobacter but without activity against Pseudomonas. TP-434 and other new analogs are unaffected by ribosomal protection Current Opinion in Pharmacology 2011, 11:433–438
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