Collaboration will focus on developing efflux pump inhibitor-based antibiotics.

Mpex Pharmaceuticals and GlaxoSmithKline partnered to develop novel medications against bacterial diseases. The alliance will focus on Mpex’s novel efflux pump inhibitors (EPI) and other technology, as well as GSK’s pipeline of novel antibiotics.

“Mpex is a company focused on the issue of antibiotic resistance and various ways of overcoming that,” Daniel D. Burgess, president and CEO of Mpex, says. “We have two main programs. Our clinical-stage program is focused on developing an aerosol formulation of the antibiotic drug levofloxacin, which is a very popular and powerful antibiotic that is currently not available in an aerosolized fashion. We’re developing that for cystic fibrosis and severe chronic bronchitis. It’s in Phase II clinical studies now and the early data looks very encouraging.”

Mpex’s second program is the EPI program, which is the subject of the GSK collaboration. Efflux pumps are protein-based transporters localized in the cytoplasmic membrane of a number of different kinds of cells. In the context of gram-negative bacteria, efflux pumps (EPs) look for any foreign materials that might enter through the bacterium’s outer membrane and pump them out before they can get through the inner membrane and destroy the bacterium. They are significant factors in multidrug and antibiotic resistance.

“This type of protection is broadly spread among all kingdoms: cancer cells protect themselves by efflux; fungal cells protect themselves from fungal drugs; bacterial cells protect themselves from antibiotics,” Olga Lomovskaya, Ph.D., Mpex’ senior director of biology, notes. “The main feature of the efflux pump is multidrug resistance—they can pick up and expel structurally dissimilar compounds from cells, so the pump can really provide a particular level of resistance to almost all antibiotics at the same time. By the same token, when you inhibit efflux pumps, many kinds of antibiotics can become more effective. The main idea is to inhibit efflux pumps to increase intracellular concentration of antibiotics or to increase the concentration of antibiotics around the target.”

The collaboration agreement with GSK revolves around developing different combinations of EPIs with different antibiotics. Burgess explained, “There are essentially seven different potential products that might come out of this, targeted at three different product profiles. Basically that’s just different groupings of bacterial organisms the antibiotics are likely to work against.”

They expect it will be utilized with existing antibiotics, but one reason GSK was interested in the collaboration with Mpex was that GSK has a number of novel antibiotics in its development pipeline. “GSK has a number of impressive new antibiotic classes they’re in the process of developing, and they have very good gram-positive activity,” Olga Lomovskaya, Ph.D., Mpex’s senior director of biology, notes. “Their activity in gram-negative organisms is limited, to some degree, by efflux pump activity. They believe that by combining their new antibiotics with EPI activity, they will open up a much broader spectrum to some of these new classes.”

Dr. Lomovskaya notes that if you examine the antibiotics currently in clinical trials, most of them demonstrate effectiveness on gram-positive bacteria, but almost none on gram-negative bacteria. “You can easily see, for example, that if you create a mutant antibiotic-resistant strain of bacteria that does not have efflux pumps, then your narrow-spectrum antibiotic acts like a broad-spectrum antibiotic. This is really improving efficacy of whatever is currently being used.”

Burgess notes that they hope to identify clinical candidates as quickly as possible. “In the optimization process, predicting timelines is fraught with peril, but we are optimistic that, in the next couple of years, we can i

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