Targets: hits and misses

Abstract number: 1133_106

Payne D.

The genomic era of antibacterial drug discovery was triggered by the completion of the H. influenzae genome in 1995. At that time, it was thought that the antibacterial therapy area was the ideal model to illustrate the ability of genomics to rapidly deliver novel mechanism medicines. Consequently, many large pharmaceutical and biotechnology companies set up genomic-based antibacterial programmes. It was generally believed that genomics would fuel a flow of targets that could be screened to rapidly identify new classes of antibiotics. This genomic exploitation was spectacularly successful in delivering hundreds of novel antibacterial strategies. A review of the literature from the last 9 years reveals a fraction of the substantial effort applied to this area, showing >35 different companies ran >120 screens on >60 different antibacterial targets. Clearly, investment in this area has been significant, but success based on the number of novel acting antibiotics in the industry pipeline is alarmingly low and there are some key scientific reasons for this poor success rate. First, screening metrics illustrate that the success of antibacterial High Throughput Screening (HTS) is significantly less productive than screening targets from other therapeutic areas. Second, optimizing hits and leads from HTS to molecules with all the requisite properties to be a safe and efficacious antibacterial can be exceptionally challenging compared to creating new generations of antibacterials from established classes where substantial background structure-activity relationships exist. Third, the initial bioinformatic and genomic analysis used to validate a target may not always extrapolate to a broader set of strains from the species or a range of target species. Consequently, a refocus of effort and resource is required to tackle antibacterial discovery in the post genomic world. Investment in new genomic technologies or novel target discovery is no longer merited. Focusing significant, consolidated medicinal chemistry and microbiology resources on advanced leads is essential for success rather than spreading effort across a large portfolio of targets. Furthermore, approaches for enhancing success at HTS and prioritizing effort on targets that are validated ‘beyond the genome’ are required. This presentation will illustrate some of the scientific challenges faced by GlaxoSmithKline in exploiting genomics to deliver new antibacterial agents and describe some of the strategies implemented in our ongoing efforts to seek new antibacterials in the post genomic world.

Session Details

Date: 01/08/2007
Time: 00:00-00:00
Session name: XXIst ISTH Congress
Location: Oxford, UK
Presentation type:
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