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Identification of new antimicrobials active in physiologically relevant media

Antibiotics are agents that disrupt biological pathways or structural integrity in order to inhibit growth or kill bacterial pathogens. Beginning with the accidental discovery of penicillin in a contaminated experiment, they have become one of the most important developments in medicine. However in recent decades, we have seen the rapid emergence of multi-drug resistant pathogens and this accumulating burden has outpaced the discovery of new antimicrobials. Typically, antimicrobial activity assays are growth-based experiments performed in nutrient rich medium. However, these studies do not accurately represent in vivo infection, pathogenesis and treatment conditions. The cellular processes responsible for survival and growth of an organism are different depending on growth conditions. The identification of the active pathways and novel virulence factors in alternative media can provide new therapeutic targets for antibiotic development. We are evaluating the antimicrobial susceptibility and RNA transcriptomes of ESKAPE pathogens in standard laboratory media, human serum, and pulmonary surfactant. In addition, we are screening small molecule libraries to identify compounds with antimicrobial activity specific to bacteria grown in physiologically relevant media. In the future, antimicrobial drug discover campaigns should consider alternative growth conditions as a means of prioritizing/triaging molecules of interest.

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