Efflux Pump Inhibitor Program

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 and lead 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) links to an outer membrane porin channel (e.g., TolC) by a membrane fusion protein (e.g., AcrA) that brings these two components into contact. 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.

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 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.

EPI Pipeline Programs

Systemic Antibiotic + EPI Program:

Mpex is developing a fixed-combination drug product consisting of an existing antibiotic and an EPI for systemic treatment of serious hospital-acquired infections due to multi-drug resistant (MDR) gram-negative bacterial pathogens (particularly Pseudomonas aeruginosa), including nosocomial pneumonia, complicated skin & skin structure infections, and other hospital-based infections due to gram-negative bacteria. Several classes of antibiotics are being evaluated in preclinical studies as potential combination therapies for serious hospital-acquired infections.

Ophthalmic Antibiotic + EPI Program:

Mpex is also developing a fixed-combination drug product of an antibiotic and an EPI for ophthalmic use. This combination approach is projected to significantly improve the potency of existing broad-spectrum antibiotics against gram-negative bacteria. Of particular importance is enhanced potency against Pseudomonas aeruginosa, a pathogen responsible for keratitis and corneal ulcers resulting from ophthalmic surgery and contact-lens use. By increasing gram-negative potency to an already broad spectrum ophthalmic antibiotic, Mpex's EPI/AB ophthalmic drops could be the broadest, most active agents available for treatment and prophylaxis of serious bacterial infections in the eye.