Efflux Pump Inhibitor Program

Bacterial Efflux Pumps

Antibiotic efflux was first discovered in the 1980s when investigating mechanisms for resistance to tetracycline antibiotics in Enterobacteriaceae. Subsequent work showed that almost all antibiotics are subject to efflux-based resistance, and that multiple pumps may be present in a pathogen that leads to multi-drug resistance. Several families of bacterial drug efflux pumps have been identified; however, efflux pumps of the Resistance/Nodulation/Cell Division Family (RND) are the most clinically relevant pumps in gram-negative bacteria. These pumps consist of a complex of three component structures that traverse the periplasmic space between the inner and outer membranes of gram-negative bacteria (see below). The inner membrane pump (e.g., AcrB) is linked to the outer membrane porin channel (e.g., TolC) by a membrane fusion protein (e.g., AcrA).This structural organization allows extrusion of antibiotics from the cytoplasmic and periplasmic compartments into the external environment, effectively reducing the concentration of drug in the bacterial cell.

Mpex Efflux Pump Inhibitor Program

The importance of bacterial efflux pumps in resistance to antibacterial drugs, and the potential for restoring antibiotic activity by their inhibition is well established. Mpex is a leader in the field of efflux pump research and has a proprietary platform of small molecule EPIs of several chemical classes. These compounds inhibit one or multiple bacterial efflux pumps, and in preclinical studies can reverse efflux-mediated resistance to many classes of antibiotics in gram-negative bacteria. EPIs in combination with an antibiotic have been shown to increase antibacterial potency against clinical isolates of gram-negative bacteria, and lower the frequency of emergence of drug resistance in vitro and in vivo, particularly in Pseudomonas aeruginosa. Potentiation by different classes of Mpex compounds has been demonstrated with several classes of drugs, including ß-lactams, oxazolidinones, fluoroquinolones and macrolides.

Mpex’s lead EPI compounds are now being optimized in anticipation of selecting development candidates. In 2008, Mpex entered into an alliance with GlaxoSmithKline on this program to develop multiple fixed-combination drug products consisting of an antibiotic and an EPI for systemic treatment of serious infections due to multi-drug resistant (MDR) gram-negative bacterial pathogens.