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

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Presentation on theme: "How Difficult Is It to Discover New Novel Antibacterials? How Difficult Is It to Discover New Antibacterials? Lynn L. Silver, Ph.D. LL Silver Consulting,"— Presentation transcript:

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

2 2 Antibacterials at FDA 2000-2011 CompoundUsageClass Active versus resistance Discovery of class Fail at FDAPass at FDA LinezolidSystemic IV/oralOxazolidinones MRSA1978 2000 ErtapenemSystemic IV/IMCarbapenem 1976 2001 CefditorenSystemic oralCephalosporin 1948 2001 GemifloxacinSystemic oralFluoroquinolone 1961 2003 DaptomycinSystemic oralLipopeptide MRSA1987 2003 TelithromycinSystemic oralMacrolide+Ery R S. pneumo1952 2004 TigecyclineSystemic IVTetracycline+Tet R 1948 2005 FaropenemSystemic oralPenem 19782006 RetapamulinTopicalPleuromutilin MRSA1952 2007 DalbavancinSystemic IVGlycopeptide 19532007 DoripenemSystemic IVCarbapenem 1976 2007 OritavancinSystemic IVGlycopeptide+VRE19532008 CethromycinSystemic oralMacrolide+Ery R S. pneumo19522009 IclaprimSystemic IVTrimethoprim+Trm R 19612009 BesifloxacinOphthalmicFluoroquinolone 1961 2009 TelavancinSystemic IVGlycopeptide+VRE1953 2009 CeftobiproleSystemic IVCephalosporin+MRSA19482009 CeftarolineSystemic IVCephalosporin+MRSA1948 2010 FidaxomicinOral CDADLipiarmycin 1975 Due soon

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

4 4 Discovery Strategies 1935 1940 1945 1955 1950 1965 1960 1970 1975 1980 1985 1990 1995 2000 2005 Whole cell phenotypic screens Empirical kill the bug screens The Golden Age Enzyme and binding assays Genomics IDs novel conserved targets Microbial physiology, biochemistry and genetics used to ID antibiotic targets and essential genes 2010 Screening for and design of novel antibacterials was vigorously pursued by Big Pharma until recently

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

6 6 Gene-to-Drug Approach Novel antibacterial targets High Throughput Screening Candidates Genomics Small molecule Hits Preclinical testing Clinical Trials Small molecule Leads Drug Inhibit the enzyme Inhibit bacterial growth Small molecule Hits Small molecule Leads Inhibit bacterial growth by inhibiting the enzyme Druglike properties Low resistance potential Compounds kill by other means Compounds cant enter Same as for other drugs Almost all have high resistance potential ez ab ez ab Candidates

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

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

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

10 10 Single Enzyme Targets of Antibiotics in Clinical Use ANTIBIOTICTARGET rifampicinRNA polymerase isoniazidInhA streptomycin30s ribosome/rpsL trimethoprimDHFR (FolA) sulfamethoxazolePABA synthase (FolP) novobiocinDNA gyrase B subunit mupirocinIle tRNA-synthetase fosfomycinMurA All are subject to single-step high level resistance USE Multi-drugTB therapy Combo w/ Sulfas Combo w/ Trimethoprim Multi-drug therapy Topical therapy UTI

11 11 Based on existing antibacterial drugs… Successful monotherapeutic antibacterials Successful monotherapeutic antibacterials Not subject to single-site mutation to high level resistance because they are multi-targeted Not subject to single-site mutation to high level resistance because they are multi-targeted Current drugs inhibiting single enzymes Current drugs inhibiting single enzymes Generally used in combination because they are subject to single mutation to significant resistance 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 … 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 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 Standardize the use of models for evolution of resistance under therapeutic conditions To validate targets, test target/lead pairs in these models To validate targets, test target/lead pairs in these models Pursue multitargets Pursue multitargets

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

14 14

15 15 Antibacterials Are Chemically Unlike other Drugs Mammalian targets antibacterial targets Mammalian targets antibacterial targets Many antibacterials must enter bacterial cells Many antibacterials must enter bacterial cells gram negative gram positive only other drugs + MW = SIZE cLogD 7.4 = GREASINESS

16 16 MW = SIZE cLogP = Greasiness Cytoplasm-targeted antibacterials Gram positive only Cytoplasmic Gram negative cytoplasmic entry by diffusion Gram negative cytoplasmic carrier-mediated transport

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

18 18 What is Antibacterial Multitargeting? GlcNAc MurNAc PP-C 55 Gyrase Topo IV Lipid II ciprofloxacin daptomycin vancomycin gentamicin tetracycline chloramphenicol linezolid erythromycin Targeting the products of multiple genes – or the product of their function – such that single mutations cannot lead to high level resistance Two or more essential gene products with similar active sites: DNA Gyrase & Topisomerase IV Two or more essential gene products with similar active sites: DNA Gyrase & Topisomerase IV Products of identical genes : rRNA Products of identical genes : rRNA Essential structures produced by a pathway where structural changes cannot be made by single mutations: Membranes Essential structures produced by a pathway where structural changes cannot be made by single mutations: Membranes These and other known multiargets have been pursued These and other known multiargets have been pursued More may be uncovered by computation based on structural studies of bacterial proteins and the small molecule ligands that bind to them More may be uncovered by computation based on structural studies of bacterial proteins and the small molecule ligands that bind to them


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