Activity-Based Protein Profiling Reveals That Cephalosporins Selectively Active on Non-replicating Mycobacterium tuberculosis Bind Multiple Protein Families and Spare Peptidoglycan Transpeptidases

Landys Lopez Quezada, Robert Smith, Tania J. Lupoli, Zainab Edoo, Xiaojun Li, Ben Gold, Julia Roberts, Yan Ling, Sae Woong Park, Quyen Nguyen, Frank J. Schoenen, Kelin Li, Jean Emmanuel Hugonnet, Michel Arthur, James C. Sacchettini, Carl Nathan, Jeffrey Aubé

Research output: Contribution to journalArticlepeer-review

Abstract

As β-lactams are reconsidered for the treatment of tuberculosis (TB), their targets are assumed to be peptidoglycan transpeptidases, as verified by adduct formation and kinetic inhibition of Mycobacterium tuberculosis (Mtb) transpeptidases by carbapenems active against replicating Mtb. Here, we investigated the targets of recently described cephalosporins that are selectively active against non-replicating (NR) Mtb. NR-active cephalosporins failed to inhibit recombinant Mtb transpeptidases. Accordingly, we used alkyne analogs of NR-active cephalosporins to pull down potential targets through unbiased activity-based protein profiling and identified over 30 protein binders. None was a transpeptidase. Several of the target candidates are plausibly related to Mtb’s survival in an NR state. However, biochemical tests and studies of loss of function mutants did not identify a unique target that accounts for the bactericidal activity of these beta-lactams against NR Mtb. Instead, NR-active cephalosporins appear to kill Mtb by collective action on multiple targets. These results highlight the ability of these β-lactams to target diverse classes of proteins.

Original languageEnglish (US)
Article number1248
JournalFrontiers in Microbiology
Volume11
DOIs
StatePublished - Jun 23 2020

Keywords

  • ABPP
  • M. tuberculosis
  • cephalosporin
  • click chemistry
  • non-replicating
  • β-lactams

ASJC Scopus subject areas

  • Microbiology
  • Microbiology (medical)

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