Rational structural modification of the isatin scaffold to develop new and potent antimicrobial agents targeting bacterial peptidoglycan glycosyltransferase.

Journal: RSC advances
Published Date: May 19, 2021

Abstract

A series of isatin derivatives bearing three different substituent groups at the N-1, C-3 and C-5 positions of the isatin scaffold were systematically designed and synthesized to study the structure-activity relationship of their inhibition of bacterial peptidoglycan glycosyltransferase (PGT) activity and antimicrobial susceptibility against , and methicillin-resistant (MRSA (BAA41)) strains. The substituents at these sites are pointing towards three different directions from the isatin scaffold to interact with the amino acid residues in the binding pocket of PGT. Comparative studies of their structure-activity relationship allow us to gain better understanding of the direction of the substituents that contribute critical interactions leading to inhibition activity against the bacterial enzyme. Our results indicate that the modification of these sites is able to maximize the antimicrobial potency and inhibitory action against the bacterial enzyme. Two compounds show good antimicrobial potency (MIC = 3 μg mL against and MRSA; 12-24 μg mL against ). Results of the inhibition study against the bacterial enzyme ( PBP 1b) reveal that some compounds are able to achieve excellent inhibitions of bacterial enzymatic activity (up to 100%). The best half maximal inhibitory concentration (IC) observed among the new compounds is 8.9 μM.

Authors

  • Yong Wang
    State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University Hunghom Kowloon Hong Kong P. R. China kwok-yin.wong@polyu.edu.hk.
  • Zhiguang Liang
    State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University Hunghom Kowloon Hong Kong P. R. China kwok-yin.wong@polyu.edu.hk.
  • Yuanyuan Zheng
    State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University Hunghom Kowloon Hong Kong P. R. China kwok-yin.wong@polyu.edu.hk.
  • Alan Siu-Lun Leung
    State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University Hunghom Kowloon Hong Kong P. R. China kwok-yin.wong@polyu.edu.hk.
  • Siu-Cheong Yan
    State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University Hunghom Kowloon Hong Kong P. R. China kwok-yin.wong@polyu.edu.hk.
  • Pui-Kin So
    State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University Hunghom Kowloon Hong Kong P. R. China kwok-yin.wong@polyu.edu.hk.
  • Yun-Chung Leung
    State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University Hunghom Kowloon Hong Kong P. R. China kwok-yin.wong@polyu.edu.hk.
  • Wing-Leung Wong
    State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University Hunghom Kowloon Hong Kong P. R. China kwok-yin.wong@polyu.edu.hk.
  • Kwok-Yin Wong
    State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University Hunghom Kowloon Hong Kong P. R. China kwok-yin.wong@polyu.edu.hk.

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