Photoaffinity labeling of benzophenone-containing salicylanilide compounds to give an insight into the mechanism in disrupting peptidoglycan formation

  • Bioorg Med Chem. 2022 Aug 1;67:116819. doi: 10.1016/j.bmc.2022.116819.
Hao-Chun Chuang  1 ,  Ming-Fang Liu  1 ,  Hsin-Yi Wu  2 ,  Ying-Ta Wu  3 ,  Ting-Jen Rachel Cheng  3 ,  Jim-Min Fang  4
Affiliations
  • 1. Department of Chemistry, National Taiwan University, Taipei 106, Taiwan, ROC.
  • 2. Instrumentation Center, College of Science, National Taiwan University, Taipei 106, Taiwan, ROC.
  • 3. The Genomics Research Center, Academia Sinica, Taipei 115, Taiwan, ROC.
  • 4. Department of Chemistry, National Taiwan University, Taipei 106, Taiwan, ROC; The Genomics Research Center, Academia Sinica, Taipei 115, Taiwan, ROC. Electronic address: [email protected].
PMID: 35635930 DOI: 10.1016/j.bmc.2022.116819
Abstract

A series of salicylanilide compounds was previously identified as Antibacterial agents that inhibit the peptidoglycan formation. To find the exact binding mode, we synthesized a benzophenone-containing salicylanilide compound (1) and used it as a photoaffinity probe to label Acinetobacter baumannii penicillin-binding protein (PBP1b). After incubation and photo-irradiation, the labeled protein was subjected to trypsin digestion, dialysis enrichment, LC-ESI-MS/MS analysis, and Mascot search to reveal an octadecapeptide sequence 364RQLRTEYQESDLTNQGLR381 that was labeled at E372. Our molecular docking experiments suggest a hydrophobic pocket surrounded by R367 and E372 is the binding site of salicylanilide 1. The pocket lies in between the transglycosylase and transpeptidase domains, thus binding of salicylanilide 1 can block the propagation pathway to disrupt the growth of peptidoglycan chain.

Keywords
Antibacterial agent; Molecular docking; Peptidoglycan; Photoaffinity labeling; Salicylanilide compound.
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