How Difficult Is It to Discover New Novel

Transcript:How Difficult Is It to Discover New Novel:
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 Antibacterials at FDA 2000-2011 Discovery Timeline fusidic acid polymyxin oxazolidinones daptomycin carbapenem monobactams mupirocin fosfomycin streptogramins nalidixic acid rifamycin trimethoprim vancomycin novobiocin cycloserine lincomycin chloramphenicol streptomycin bacitracin penicillin sulfonamide metronidazole 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 Discovery Strategies The Golden Age 2010 Screening for and design of novel antibacterials was vigorously pursued by Big Pharma until recently 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 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 can’t enter Same as for other drugs Almost all have high resistance potential ez ab ez ab Candidates 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 The Obstacles to Antibacterial Discovery -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 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 Antibacterials Useful in Systemic Monotherapy ANTIBACTERIAL TARGET -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