The antibiotic pipeline is broken, with a dearth of new antibiotics, a collapse in pharmaceutical company research1, and the exhaustion of chemical diversity contained in pharma libraries. “The low hanging fruit from the antibiotic tree has probably already been picked and new sources of compounds are needed.”2 This talk will illustrate three different approaches we have been investigating to uncover and develop new antibiotics:

1) In order to discover new therapies, the rational evolution of existing antibiotics has proven to be more effective than screening for new structures. We postulated that membrane-targeting motifs could be appended to drugs acting on membrane-anchored targets, enhancing membrane binding and concomitantly increasing drug concentration at the target site. We selected vancomycin to test this approach, as this prototypical glycopeptide inhibits peptidoglycan formation by binding membrane-bound lipid II. An comprehensive medicinal chemistry campaign has prepared over 300 analogues, leading to promising candidates that have been extensively characterised.
2) During the ‘golden age’ of antibiotic discovery, many potentially promising compounds were discovered but never developed. We have been investigating the octapeptins, naturally derived products similar to the commonly prescribed polymyxin antibiotics. The octapeptins show promising broad-spectrum activity against Gram-negative bacteria, most importantly against polymyxin-resistant species.
3) Antibacterial drugs occupy a unique property space that is vastly different to drugs developed for other therapeutic areas, suggesting that commercially available chemical compounds designed for ‘druglike’ properties lack the physicochemical properties ideal for activity against bacteria and therefore, alternate sources of chemical diversity need to be investigated. We believe that there is an untapped resource contained in the laboratories of synthetic organic chemists; compounds prepared for other projects that have never been tested for their antimicrobial potential. We have created a Wellcome Trust-supported not-for-profit open-access pipeline, The Community for Open Antimicrobial Drug Discovery [CO-ADD] as a global screening initiative to uncover this significant and rich chemical diversity, providing unencumbered free antimicrobial screening for any interested researcher.