What happened to natural product antibacterial drug discovery and why?

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1 What happened to natural product antibacterial drug discovery and why? Mike Dawson Antibiotic Action 21 st May 1

2 Newly reported natural products Natural product screening in Pharma is no more Reports of new natural products in the Journal of Antibiotics: Diversification of therapeutic areas Predominance of Asian Institutes. Shift from Japan to Korea/China Industry SME/CRO Academia Kyowa Hakko Squibb Sanraku-Ocean Shionogi Nippon Roche Upjohn BMS Japan Fujisawa Merck Pfizer Toyo Jozo Shionogi Kyowa Hakko Pfizer Japan Wyeth Sankyo Taisho Shionogi Yamanouchi Novartis Mycosynthetix NAICONS AMRI Merlion TMS 2

3 What has happened to the big Pharma NP legacy? (1) Clinical pipeline is dominated by further derivs. of established NP series: From natural leads... Glycopeptides 3 Lipopeptides 2 Thiopeptide Pleuromutilin Tetracycline 3 Aminoglycoside 2 Cephalosporin Carbapenem Penem Monobactam β-lactamase inhibitor Ketolide Peptide mimetics 2 Lantibiotic Synthetic leads... Oxazolidinones 3 Quinolones 7 Oxazol-quinolone PDF inhibitor Fab I inhibitor 3 LpxC inhibitor Clostridium-specific Met trna inhibitor β-lactamase inhibitor 2 None based on new (natural) series discovered in last 20 years 3

4 What has happened to the big Pharma NP legacy? (2) Externalised leads: Big Pharma leads licensed and developed by SMEs/speciality pharmas: Daptomycin (Cubist) ex Lilly Friulimicin (Merlion) ex Aventis Sordarins (Diversa) ex Glaxo Wellcome Specialised spin-outs: Basilea, Novexel Other successes from old NP leads: Fidaxomicin (Optimer) Pleuromutilins (Nabriva) 4

5 What has happened to the big Pharma NP legacy? (3) Lead discovery/source collections: CROs: IMD, AMRI, Hypha, Analyticon etc.. SMEs: NAICONS, Merlion Not-for-profits: Natural Products Discovery Institute, Medina Academia:??? Do these entities have the capability to make a sustainable contribution or are they just playing out ex-pharma assets? 5

6 Summarising the current status Major effort on new derivatives of established NP series Some effort on bringing through old leads from historical pharma efforts to make new drugs Some continued discovery efforts in CROs and not-for-profits but mainly using frozen assets from pharma No effective sustainable discovery efforts for new natural product series 6

7 Why did Pharma stop screening natural products? Belief that other technologies would provide Preference for design over serendipity Associated with anti-infectives and their poor business case Low productivity Believed incompatible with rapid lead optimisation Poor logistic fit with lead discovery processes Desire for Lipinski-compliant leads with oral bioavailability 7

8 Why did productivity decline and is it reversible? Potent, whole cell active antibacterials produced in good quantity by common fast growing microorganisms from readily accessible environments are probably exhausted If we collect fast growing streptomycetes from soil, culture them conventionally, and screen for potent antibacterials we are unlikely to find much that is new Target-based screening could have been the answer, but whole cell activity proved an unsurmountable barrier. Uptake features need to be built into the lead not added on afterwards 8

9 Is it just a numbers game? If you want to look at the usual sources in the conventional way for potent antibacterials then the answer is probably yes! 9

10 New sources Slow growing microorganisms, new culture techniques Uncultured organisms, metagenomics Microbes in symbiotic relationships in plants, other organisms Marine macro and microorganisms Pharmamar/Zeltia, Aquapharm New culture techniques/genetic interventions that lead to expression of cryptic pathways 10

11 New screening methods Information rich whole cell screening is crucial to future of finding new leads Elitra/Merck, Discuva Prioritisation of actives is driven by MOA not just amount and potency All leads already have uptake features built in Also allows effective mining of already indentified NPs Availability of compounds and cultures (importance of culture collections) Must be allied with a willingness to take on difficult chemistry of improving less potent leads Biosynthetic manipulation may help 11

12 New technology Automation/high-throughput techniques LC-UV-MS based dereplication Rapid structure elucidation cryoprobe/sensitive nmr techniques 12

13 Information-rich whole cell screening test capillary electrophoresis 20 generations multiplex PCR bacterial strains (antisense knockdowns) mock data analysis 13

14 The importance of a knowledge of SAR H O H O OH HO H O OH O OMe Sordarin Sandoz 1968 MIC C.albicans 8μg/ml MOA unknown No interest as drug lead No further publications for 30 years 1998 Merck and GW scientists identify as selective protein synthesis Inhibitor (EF2) Identify natural esters with potent activity Chemical programmes in: Glaxo Wellcome Merck Banyu Fujisawa BMS Sankyo 14

15 What could new generation natural productbased antibacterial drug discovery look like? Range of sources including innovative microorganism isolation and culturing, metagenomics Information rich whole cell screening Effective dereplication of actives and rapid structural determination Smart chemistry/biosynthetic manipulation to optimise leads 15

16 The challenges Tools are available for effective discovery of new NP scaffolds We ve exhausted the easy but have developed methods to tackle the more difficult But, never assembled together and optimised. Cost effectiveness still a big challenge (and risky) Unlikely to see necessary investment from big Pharma or private equity for centralised effort Long time-scales mean original innovators are not always beneficiaries Massive contribution to knowledge base underpins drug research generally Need for a new model to move forward 16