Structure-Activity Relationship of Penem Antibiotic Side Chains Used against Mycobacteria Reveals Highly Active Compounds

Hunter R. Batchelder, Trevor A. Zandi, Amit Kaushik, Akul Naik, Elizabeth Story-Roller, Emily C. Maggioncalda, Gyanu Lamichhane, Eric L. Nuermberger, Craig A. Townsend

Research output: Contribution to journalArticlepeer-review

Abstract

The rise of antibiotic-resistant Mycobacterium tuberculosis and non-tuberculous mycobacterial infections has placed ever-increasing importance on discovering new antibiotics to treat these diseases. Recently, a new penem, T405, was discovered to have strong antimicrobial activity against M. tuberculosis and Mycobacteroides abscessus. Here, a penem library of C2 side-chain variants was synthesized, and their antimicrobial activities were evaluated against M. tuberculosis H37Rv and M. abscessus ATCC 19977. Several new penems with antimicrobial activity stronger than the standard-of-care carbapenem antibiotics were identified with some candidates improving on the activity of the lead compound, T405. Moreover, many candidates showed little or no increase in the minimum inhibitory concentration in the presence of serum compared to the highly protein-bound T405. The penems with the strongest activity identified in this study were then biochemically characterized by reaction with the representative l,d-transpeptidase LdtMt2 and the representative penicillin-binding protein d,d-carboxypeptidase DacB2.

Original languageEnglish (US)
Pages (from-to)1627-1636
Number of pages10
JournalACS Infectious Diseases
Volume8
Issue number8
DOIs
StatePublished - Aug 12 2022

Keywords

  • M. abscessus
  • M. tuberculosis
  • antibiotic
  • penem
  • structure-activity relationship
  • β-lactam

ASJC Scopus subject areas

  • Infectious Diseases

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