Overcoming scientific and structural bottlenecks in antibacterial discovery and development

Figures & data

Box 1. Case study of Ramoplanin™ with relevant dates tracking the discovery, patent, out-licencing, and changing ownership of the molecule.

1980	Patent, Gruppo Lepetit SpA/Aventis
1984	First published paper
1996	Buyout of Lepetit from Aventis by Biosearch Italia
1997–2001	More patents taken by Biosearch
1999	Intrabiotics starts phase II studies
2001	Presentation of in vitro data (C. difficile, VRE) at ICAAC
2001	Ramoplanin gets EMA Orphan drug designation
2001	Biosearch reacquires rights to oral Ramoplanin from Intrabiotics. Intrabiotics had completed phase II trials but failed to recruit patients for phase III (104/950 needed)
2001	Genome Therapeutics acquires licence for oral (not topical) Ramoplanin and planned to complete phase III trial
2002	Biosearch reacquires rights to topical Ramoplanin from Intrabiotics
2002	Versicor buys Biosearch
2003	Versicor changes name to Vicuron
2004	Genome Therapeutics gets FDA fast-track status for Ramoplanin
2004	Genome Therapeutics changes name to Oscient
2005	Pfizer buys Vicuron
2005	Oscient gets Special Protocol Assessment from the FDA, needs to complete 2 phase III trials for VRE
2006	Oscient acquires world-wide rights for Ramoplanin from Pfizer/Vicuron
2007	Oscient receives Notice of allowance from the FDA for methods of use for C. difficile
2009	Oscient declares bankruptcy
Dec 2009	Nanotherapeutics acquires rights to Ramoplanin

Box 2. Proposed research questions that could be explored to aid easier antibiotic discovery.

The entry/exit problems

• Methods to measure entry of molecules into (Gram-negative) bacteria are needed—there are some tentative thoughts that mass spectrometry may be a way forward, but the methods are a long way from being truly useful (28) • Develop rules, like an antibacterial version of ‘Lipinsky’s rule of 5′ for cytoplasmic entry into Gram-negative bacteria • Studies of self-promoted uptake, including investigating more closely the surface structure and charge of the outer membrane in Gram-negatives • Investigate more closely which properties that make molecules substrate for efflux pumps

Chemical novelty • Better screening libraries are needed, keeping in mind that antibacterials in general have been found to have differing chemical properties than other pharmaceuticals (29). Maybe virtual screens of compounds, e.g. in PubChem, could be useful as a first step, much like that performed at the University of Dundee for neglected diseases (30) • Create new, more varied libraries—however, diversity can mean many different things, and it needs to be defined how best to achieve diversification • New libraries could also be created by going back to natural products and finding new sources of compounds such as slow-growing micro-organisms, marine bacteria, or products of cryptic pathways. The molecules need to be coupled with whole-cell screens and assays that allow for effective de-replication of already discovered natural products (31)

Avoiding resistance

• Increase fundamental knowledge of under what circumstances (clinically relevant) resistance mutations arise • Finding ways of ‘reversing’ resistance other than beta-lactamase and efflux pump inhibitors, such as perhaps inactivating the Cfr-methylase that gives resistance to a variety of ribosome-directed drugs • Better animal models are needed, to understand better the correlation between in vitro and in vivo resistance data. Tests for efficacy usually involve a loading dose of ∼10^3–10^5 bacteria, so resistance events, occurring a frequency of 1 in 10^7 or less, may rarely be picked up

Other

• Methods to test the usefulness of anti-virulence approaches in vivo, perhaps by using engineered strains that can turn off virulence factors during an infection • Investigate which panel(s) of strains that are the most relevant to test new antibiotics against • Address the lack of structural data for many bacterial proteins

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