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

Hao-Chun Chuang; Ming-Fang Liu; Hsin-Yi Wu; Ying-Ta Wu; Ting-Jen Rachel Cheng; Jim-Min Fang

doi:10.1016/j.bmc.2022.116819

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. Epub 2022 May 13.

Authors

Hao-Chun Chuang¹, Ming-Fang Liu¹, Hsin-Yi Wu², Ying-Ta Wu³, Ting-Jen Rachel Cheng³, Jim-Min Fang⁴

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Benzophenones / pharmacology
Escherichia coli / metabolism
Molecular Docking Simulation
Peptidoglycan
Peptidoglycan Glycosyltransferase* / chemistry
Peptidoglycan Glycosyltransferase* / metabolism
Photoaffinity Labels
Salicylanilides
Tandem Mass Spectrometry

Substances

Benzophenones
Peptidoglycan
Photoaffinity Labels
Salicylanilides
Peptidoglycan Glycosyltransferase