Challenges in Discovering Novel Antibacterials

Lynn L. Silver, Ph.D., discusses the difficulties in discovering new antibacterials, highlighting the limited success in bringing novel classes to the clinic in recent years. The timeline and strategies for antibacterial discovery by Big Pharma are explored, along with potential solutions to overcome scientific obstacles.

• Antibacterials
• Discovery
• Pharmaceutical Industry
• Challenges
• Novel Classes

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1. How Difficult Is It to Discover New Novel Antibacterials? Antibacterials? Lynn L. Silver, Ph.D. LL Silver Consulting, LLC How Difficult Is It to Discover New

2. 2 Antibacterials at FDA 2000-2011 Compound Usage Class Active versus resistance MRSA Discovery of class 1978 Fail at FDA Pass at FDA Linezolid Systemic IV/oral Oxazolidinones 2000 Ertapenem Systemic IV/IM Carbapenem 1976 2001 Cefditoren Systemic oral Cephalosporin 1948 2001 Gemifloxacin Systemic oral Fluoroquinolone 1961 2003 Daptomycin Systemic oral Lipopeptide MRSA 1987 2003 EryR S. pneumo Telithromycin Systemic oral Macrolide+ 1952 2004 TetR Tigecycline Systemic IV Tetracycline+ 1948 2005 Faropenem Systemic oral Penem 1978 2006 Retapamulin Topical Pleuromutilin MRSA 1952 2007 Dalbavancin Systemic IV Glycopeptide 1953 2007 Doripenem Systemic IV Carbapenem 1976 2007 Oritavancin Systemic IV Glycopeptide+ VRE 1953 2008 EryR S. pneumo Cethromycin Systemic oral Macrolide+ 1952 2009 TrmR Iclaprim Systemic IV Trimethoprim+ 1961 2009 Besifloxacin Ophthalmic Fluoroquinolone 1961 2009 Telavancin Systemic IV Glycopeptide+ VRE 1953 2009 Ceftobiprole Systemic IV Cephalosporin+ MRSA 1948 2009 Ceftaroline Systemic IV Cephalosporin+ MRSA 1948 2010 Fidaxomicin Oral CDAD Lipiarmycin 1975 Due soon

3. 3 Fidaxomicin Discovery Timeline 2010 Retapamulin 2005 Last novel agent to reach the clinic was discovered in 1987 Linezolid Daptomycin Synercid 2000 Bactroban 1995 daptomycin 1990 Norfloxacin Imipenem monobactams 1985 1980 lipiarmycin oxazolidinones carbapenem cephamycin 1975 fosfomycin 1970 mupirocin lincomycin fusidic acid 1965 metronidazole novobiocin cycloserine isoniazid nalidixic acid trimethoprim 1960 rifamycin vancomycin 1955 erythromycin Although development and modification of old classes has proceeded no newly discovered novel classes have made it to the clinic in 24 years cephalosporin bacitracin streptogramins pleuromutilin 1950 chlortetracycline chloramphenicol 1945 polymyxin streptomycin 1940 1935 sulfonamide 1930 penicillin

4. 4 Discovery Strategies 2010 2005 2000 1995 1990 1985 1980 1975 1970 1965 1960 1955 Screening for and design of novel antibacterials was vigorously pursued by Big Pharma until recently 1950 1945 1940 1935

5. 5 Consider If Big Pharma (and biotechs) have been largely unsuccessful in finding novel antibacterials to develop Will that be reversed by Increasing financial incentives? Revising regulatory policy? What has prevented novel discovery? The need to address scientific obstacles

6. 6 Genomics Gene-to-Drug Approach Novel antibacterial targets High Throughput Screening Inhibit the enzyme Small molecule Hits Small molecule Hits Inhibit bacterial growth Small molecule Leads Small molecule Leads Inhibit bacterial growth by inhibiting the enzyme ez ab Candidates Candidates ab ez Preclinical testing Druglike properties Low resistance potential Clinical Trials Drug

7. 7 The Obstacles to Antibacterial Discovery Improve chemical sources Remove toxic, detergent, reactive compounds from libraries Define physicochemical characteristics specifying bacterial entry & efflux Revive natural product screening Pursue targets with low resistance potential

8. 8 -lactams Glycopeptides Cycloserine Fosfomycin The bacterial entry problem CM Rifampin P. Aeruginosa is more problematic due to strong efflux and reduced permeability Aminoglycosides Tetracyclines Chloramphenicol Macrolides Lincosamides Oxazolidinones Fusidic Acid Mupirocin Gram negative P. aeruginosa gram positive Periplasm Cytoplasm Cytoplasm Novobiocin Fluoroquinolones Sulfas Trimethoprim Metronidazole Impermeability and efflux of G- render many agents inactive CM Daptomycin Polymyxin Almost all gram positive drugs are active (biochemically) on the analogous gram negative targets but the drugs are not antibacterial vs gram negatives OM

9. 9 Antibacterials Useful in Systemic Monotherapy Targets with low resistance potential ANTIBACTERIAL -lactams Glycopeptides Tetracycline Aminoglycosides Macrolides Lincosamides Chloramphenicol Oxazolidinones Fluoroquinolones Metronidazole Daptomycin TARGET multiple penicillin binding proteins [PBPs] synthesis of cell wall peptidoglycan D-ala-D-ala of peptidoglycan substrate rRNA of 30s ribosome subunit rRNA of 30s ribosome subunit rRNA of 50s ribosome subunit rRNA of 50s ribosome subunit rRNA of 50s ribosome subunit rRNA of 50s ribosome subunit bacterial topoisomerases (gyrase and topo IV) DNA membranes Examine successful antibacterials enzymes All have multiple targets or targets encoded by multiple genes No high-level resistance by single-step mutation

10. 10 Single Enzyme Targets of Antibiotics in Clinical Use USE ANTIBIOTIC TARGET Multi-drugTB therapy rifampicin RNA polymerase Multi-drug TB therapy isoniazid InhA Multi-drug TB therapy streptomycin 30s ribosome/rpsL Combo w/ Sulfas trimethoprim DHFR (FolA) Combo w/ Trimethoprim sulfamethoxazole PABA synthase (FolP) Multi-drug therapy novobiocin DNA gyrase B subunit Topical therapy mupirocin Ile tRNA-synthetase UTI fosfomycin MurA All are subject to single-step high level resistance

11. 11 Based on existing antibacterial drugs Successful monotherapeutic antibacterials Not subject to single-site mutation to high level resistance because they are multi-targeted Current drugs inhibiting single enzymes Generally used in combination because they are subject to single mutation to significant resistance THUS: "Multitargets" are preferable to single enzyme targets for systemic monotherapy BUT: The search for single enzyme inhibitors has been the mainstay of novel discovery for at least 20 years

12. 12 If single enzyme targets give rise to resistance in the laboratory Determine if the in vitro (laboratory) resistance is likely to translate to resistance in the clinic Standardize the use of models for evolution of resistance under therapeutic conditions To validate targets, test target/lead pairs in these models Pursue multitargets

13. 13 A way forward Targets For single-enzyme inhibitors: Robust modeling of resistance Pursue multi-targets Chemicals Deduce rules for bacterial entry and efflux, especially in G- Clean up libraries and incorporate rules for entry Revive Natural Products With better chemicals, return to empirical discovery Collaboration between academe and industry Computation for multitargeting Modeling of resistance Chemistry for cell entry and efflux avoidance

14. 14

15. 15 Antibacterials Are Chemically Unlike other Drugs gram negative gram positive only + other drugs cLogD7.4 = GREASINESS MW = SIZE Mammalian targets antibacterial targets Many antibacterials must enter bacterial cells

16. 16 Cytoplasm-targeted antibacterials 8.0 Gram positive only Cytoplasmic 6.0 Gram negative cytoplasmic entry by diffusion 4.0 cLogP = Greasiness 2.0 0.0 -2.0 Gram negative cytoplasmic carrier-mediated transport -4.0 -6.0 0 200 400 600 800 1000 1200 MW = SIZE

17. 17 An approach to new multitargets: Sorting targets by their ligands Compound and fragment profiling binding/docking to bacterial proteins Can be done computationally Candidate multitargets

18. 18 What is Antibacterial Multitargeting? Targeting the products of multiple genes or the product of their function such that single mutations cannot lead to high level resistance ciprofloxacin Two or more essential gene products with similar active sites: DNA Gyrase & Topisomerase IV Products of identical genes : rRNA Gyrase Topo IV gentamicin tetracycline chloramphenicol linezolid erythromycin Essential structures produced by a pathway where structural changes cannot be made by single mutations: Membranes Lipid II GlcNAc These and other known multiargets have been pursued MurNAc PP-C55 More may be uncovered by computation based on structural studies of bacterial proteins and the small molecule ligands that bind to them vancomycin daptomycin