Optimization of a novel compound with activity against MRSA and P. aeruginosa

Project Leader

Ambrose Cheung, M.D.
Professor, Microbiology and Immunology Geisel School of Medicine

Our research is focused on the pathogenesis of S. aureus resistance mechanisms and drug discovery against resistant organisms. For drug discovery, we recently embarked on a program at the Longwood ICCB facility at Harvard where we screened novel small molecules for activity against MRSA and P. aeruginosa, two microorganisms that have been frequently implicated in pneumonia in hospitalized patients, especially those with prior lung ailment such as cystic fibrosis and COPD. The basis of our screen is that we recently found that cefoxitin which binds PBP4 can enhance the activity of MRSA to beta-lactam such as oxacillin. We thus theorize that small molecules may re-establish the sensitivity of resistant MRSA and other Gram- activity (e.g. Pseudomonas aeruginosa) again to beta-lactam antibiotics such as oxacillin and ceftriaxone. To examine this hypothesis, we performed initial screen of ~60,000 compounds in two rounds at the Longwood Drug Screening facility at Harvard Medical School to identify small molecules that can inhibit growth of MRSA USA300 in sub-MIC oxacillin. After cherry picking 26 compounds, we identified six compounds one of which, compound W, exhibits unique structures and broad spectrum activity. In collaboration with Dr. Jimmy Wu at the Department of Chemistry at Dartmouth, we will synthesize a series of analogs of compound W. The goal of this research is to obtain preliminary structure-activity relationship of these analogs and to elucidate the molecular target of compound W.