Drugs Under Investigation Target the Toxin, not the Organism, Bypassing Resistance

   Laboratory research performed at Case Western Reserve University in Cleveland holds the future possibility of creating drugs that render methicillin resistant Staphylococcus aureus (MRSA) harmless by preventing the production of its disease-causing toxins. As these drugs do not threaten the survival of the organism itself, they should not trigger  the development of resistance.

   Menachem Shoham, PhD, associate professor and researcher in the department of biochemistry at the Case Western, reported on his work at the 50th Interscience Conference on Antimicrobial Agents and Chemotherapy in Boston. He identified a bacterial protein, AgrA, as a key molecule responsible for the release of toxins in a variety of bacterial species. His search for AgrA inhibitors was initially carried out in a computer search of approximately 90,000 compounds to determine which would best fit the activation site on AgrA. Subsequently, about 100 of the best scoring compounds were acquired and tested in the laboratory for inhibition of the production of the toxin, which ruptures red blood cells.

   The effects of top-scoring compounds were monitored by qRT-PCR. Structure-activity relationship studies were subsequently conducted that led to the discovery of more potent compounds. More than a dozen active compounds have been discovered by this method. According to Dr. Shoham, the best drug candidate reduces red blood cell rupture to by nearly 90% without inhibiting bacterial growth, which could trigger the development of resistance.

   “It is possible to inhibit virulence of MRSA without killing the bacteria,” Dr. Shoham said. Looking to the future, “Such anti-pathogenic drugs may be used for prophylaxis or therapy by themselves or in combination with an antibiotic.”

   Dr. Shoham’s study was presented at a poster session on “New Discovery Methodologies.”