The evolution and dissemination of resistant Gram-negative pathogens, especially including Pseudomonas aeruginosa and Acinetobacter baumannii, represents an increasingly urgent global challenge. β-Lactam/β-lactamase inhibitor products, involving existing β-lactam antibiotics in combination with new classes of β-lactamase inhibitors, including boronic acids and diazabicyclooctanones are in clinical development to address this threat. The Buynak lab has pursued a complimentary approach, focusing instead on atypical structural modifications of the antibiotic. We have previously shown that atypical carbapenem antibiotics (i.e. carbapenems with structural modifications at positions other than C2) can possess improved properties over existing carbapenems, including improved outer membrane penetration and, in selected cases, improved resistance to carbapenemase-mediated hydrolysis. We will present an in vitro evaluation of two C1 substituted carbapenems, including their apparent lack of interaction with numerous pseudomonal efflux pumps, especially including MexAB/OprM. As judged by kcat/KM values, these new atypical C1-substituted carbapenems exhibit relative stability to human renal dehydropeptidase (DHP1).

Synthesis and evaluation of atypical C1 substituted carbapenem antibiotics which resist numerous pseudomonal efflux pumps

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.