Bacterial resistance to antibiotics is a continuing concern for clinicians around the globe. In order to overcome this problem, many have attempted to identify new chemical entities with novel mechanisms of action in an effort to combat pre-existing resistance. However, a common mechanism of resistance involves the utilization of multi-drug resistance efflux pumps, many of which are the cause clinical resistance to one or multiple classes of drugs, complicating and extending the course of treatment. These efflux pumps either utilize ATP or proton motive force (PMF) directly as a power source to remove problematic entities. Overcoming the resistance imposed by these efflux pumps would restore the action of many drugs for many pathogens. In order to overcome these multi-drug resistance efflux pumps, we’ve envisioned decoupling PMF to block bacterial metabolism and efflux. We are looking into multiple metabolic poisons that disrupt PMF to recover the action of a variety of drugs in multiple pathogens including gram-negative infectious agents and M. tuberculosis. PMF poisons, such as 2,4-dinitrophenol (DNP), can unselectively disrupt the gradient of protons over a membrane, disrupting cellular metabolism and efflux mechanisms. To overcome this limitation, we have chosen to study the effects of PMF poisons with a chemical handle which can be used to attach a targeting moiety do reduce the side-effects of the poisons. Herein we describe a limited set of PMF poisons which show synergy with FDA-approved drugs in pathogenic bacteria such as P. aeruginosa and M. tuberculosis. We will also show that β-lactam conjugates of these poisons will offer selectivity for bacteria, with β-lactamase activity, over mammalian cells using a targeted release strategy. Combining our PMF poison with known drugs has shown significant synergy with heavily resisted chemotherapeutics. In-vitro testing of our PMF poison in combination with tetracycline in checkerboard assays has shown fractional inhibitory concentrations (FIC) of each compound by 32-fold compared to monotherapies for P. aeruginosa. We will present detailed characterization of the nature of this synergy in P. aeruginosa and investigate other pathogens with similar efflux machinery.

Decoupling proton motive force to overcome antibacterial resistance

253rd National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.