Computationally designed peptide macrocycle inhibitors of New Delhi metallo-β-lactamase 1.

ABSTRACT: The rise of antibiotic resistance calls for new therapeutics targeting resistance factors such as the New Delhi metallo-β-lactamase 1 (NDM-1), a bacterial enzyme that degrades β-lactam antibiotics. We present structure-guided computational methods for designing peptide macrocycles built from mixtures of l- and d-amino acids that are able to bind to and inhibit targets of therapeutic interest. Our methods explicitly consider the propensity of a peptide to favor a binding-competent conformation, which we found to predict rank order of experimentally observed IC₅₀ values across seven designed NDM-1- inhibiting peptides. We were able to determine X-ray crystal structures of three of the designed inhibitors in complex with NDM-1, and in all three the conformation of the peptide is ve

SUBMITTER: Mulligan VK 

PROVIDER: S-EPMC8000195 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature