Project Summary / Abstract Increasing rates of antibiotic resistance in common bacterial pathogens threatens to reverse many of the gains made in human health over the past century. This proposal details a research plan designed to understand the basic biology of resistance to beta-lactam antibiotics in an important group of Gram-negative pathogens, the Enterobacterales. Aim 1 of this proposal concerns a novel, conserved protein that the candidate has discovered helps mediate beta-lactam resistance in the Enterobacterales. Through targeted experimentation and quantitative proteomics, the candidate will discover how this protein functions at the molecular level. Aim 2A takes a broader focus, seeking to characterize how many mutations are necessary to impart resistance in an important pathogen of hospitalized patients, Serratia marcescens. This is important to determine, because if this sort of resistance is difficult to acquire, it may be prudent for clinicians to use narrower, rather than broader antibiotics. Finally, in Aim 2B, the candidate strives to identify proteins and pathways necessary for a kind of intrinsic resistance that a group of Enterobacterales can utilize to become resistant to even the last-line carbapenem group of beta-lactams. This approach has the potential to identify new antibiotic targets. The candidate’s background includes training in biochemistry and eukaryotic cell biology, as well as the clinical practice of infectious diseases. This Mentored Clinical Scientist Research Career Development Award proposes additional training in genomics, proteomics, and transcriptomics necessary for an independent career investigating clinically relevant problems in the prokaryotic cell biology of antibiotic resistance. With the guidance of his co-mentors, the candidate will obtain this additional training using both formal coursework and hands-on training utilizing the best of the resources available at the Massachusetts General Hospital, Brigham and Women’s Hospital, and Harvard Medical School.

Project Narrative Antibiotic resistance in Gram-negative bacteria poses an urgent threat to human health. We will investigate how a specific conserved protein mediates resistance to the cephalosporin group of beta-lactam antibiotics, characterize how likely the important human pathogen, Serratia marcescens, is to develop resistance to cephalosporins during treatment, and identify novel proteins and pathways necessary for this kind of resistance.