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

Vikram Khipple Mulligan, Sean Workman, Tianjun Sun, Stephen Rettie, Xinting Li, Liam J. Worrall, Timothy W. Craven, Dustin T. King, Parisa Hosseinzadeh, Andrew M. Watkins, P. Douglas Renfrew, Sharon Guffy, Jason W. Labonte, Rocco Moretti, Richard Bonneau, Natalie C.J. Strynadka, David Baker

Research output: Contribution to journalArticlepeer-review


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 very close to the computationally designed model. In two of the three structures, the binding mode with NDM-1 is also very similar to the design model, while in the third, we observed an alternative binding mode likely arising from internal symmetry in the shape of the design combined with flexibility of the target. Although challenges remain in robustly predicting target backbone changes, binding mode, and the effects of mutations on binding affinity, our methods for designing ordered, binding-competent macrocycles should have broad applicability to a wide range of therapeutic targets.

Original languageEnglish (US)
Article numbere2012800118
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number12
StatePublished - Mar 23 2021


  • Antibiotic resistance | drug design | protein folding | peptide macrocycles | computational design

ASJC Scopus subject areas

  • General


Dive into the research topics of 'Computationally designed peptide macrocycle inhibitors of New Delhi metallo-β-lactamase 1'. Together they form a unique fingerprint.

Cite this