Unlocking new targets to combat antimicrobial resistance through chemical biology (360G-Wellcome-317713_Z_24_Z)

Antimicrobial resistance (AMR) is one of the most serious threats to health globally, potentially rendering medical advances including surgery and chemotherapy too dangerous to be practical. Even diseases of old age may become lessening priorities if AMR compromises treatments and shortens life expectancy. AMR is exacerbated by sparce antibiotic development pipelines, and it is widely appreciated that new molecules with novel mechanisms-of-action are urgently needed. However, new antibiotics have limited commercial markets, needing to be kept as ‘agents-of-last-resort’ for resistant infections, creating a dichotomy where antibiotics are arguably among the most valuable medical products on the planet, yet there is no financial incentive for their development. I will use interdisciplinary chemical biology to identify new drug targets, mechanisms of action, and tool molecules to combat AMR, by slowing resistance evolution or reversing resistance where it already exists. Such ‘antibiotic adjuvants’ could be paired with existing antibiotic treatments rather than being 'agents-of-last-resort', and may have wider financial markets therefore inspiring commercial investment in AMR. Key goals include developing methods to increase bacterial cell penetration, identifying druggable targets in the ‘SOS response’ to slow resistance evolution, converting existing antibiotics to inactivate resistance mechanisms, and target deconvolution for conditionally-lethal molecules.