Target based Antibacterial Drug Discovery. Zero for the 20th Century

Abstract

Armed with whole genome sequences of multiple pathogenic bacteria, large collections of synthetic small molecules and natural product extracts, increasingly sophisticated laboratory automation, high throughput genetics, long lists of essential genes, high throughput screening, crystal structures, virtual (in silico) screening and phalanxes of medicinal chemists not a single antibacterial compound, derived by target based drug discovery, has entered clinical development. Despite a considerable industrial (and to a lesser extent academic) investment the futility in discovering new antibiotics has been palpable, especially during a time of increasingly widespread multidrug resistant strains of bacteria mainly in hospitals but apparently now spreading into the community. These failures may be more apparent than real but two things are becoming clear: we do not really understand bacterial resistance, especially as the ecological problem it is; nor do we appreciate what properties a truly “valid” molecular target should possess.