Boosting the efficacy of anti-MRSA β-lactam antibiotics via an easily accessible, non-cytotoxic and orally bioavailable FtsZ inhibitor

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journal

6 Scopus Citations
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Author(s)

  • Hok Kiu Lui
  • Wei Gao
  • Kwan Choi Cheung
  • Wen Bin Jin
  • Ning Sun
  • Jason W.Y. Kan
  • Iris L.K. Wong
  • Jiachi Chiou
  • Dachuan Lin
  • Edward W.C. Chan
  • Yun-Chung Leung
  • Tak Hang Chan
  • Kin-Fai Chan
  • Kwok-Yin Wong

Detail(s)

Original languageEnglish
Pages (from-to)95-115
Journal / PublicationEuropean Journal of Medicinal Chemistry
Volume163
Online published24 Nov 2018
Publication statusPublished - 1 Feb 2019
Externally publishedYes

Abstract

The rapid emergence of methicillin-resistant Staphylococcus aureus (MRSA) strains has undermined the therapeutic efficacy of existing β-lactam antibiotics (BLAs), prompting an urgent need to discover novel BLAs adjuvants that can potentiate their anti-MRSA activities. In this study, cytotoxicity and antibacterial screening of a focused compound library enabled us to identify a compound, namely 28, which exhibited low cytotoxicity against normal cells and robust in vitro bactericidal synergy with different classes of BLAs against a panel of multidrug-resistant clinical MRSA isolates. A series of biochemical assays and microscopic studies have revealed that compound 28 is likely to interact with the S. aureus FtsZ protein at the T7-loop binding pocket and inhibit polymerization of FtsZ protein without interfering with its GTPase activity, resulting in extensive delocalization of Z-ring and morphological changes characterized by significant enlargement of the bacterial cell. Animal studies demonstrated that compound 28 had a favorable pharmacokinetic profile and exhibited potent synergistic efficacy with cefuroxime antibiotic in a murine systemic infection model of MRSA. Overall, compound 28 represents a promising lead of FtsZ inhibitor for further development of efficacious BLAs adjuvants to treat the staphylococcal infection.

Research Area(s)

  • 3-Aminobenzamides, FtsZ inhibitor, Methicillin-resistant Staphylococcus aureus, β-Lactam antibiotics

Citation Format(s)

Boosting the efficacy of anti-MRSA β-lactam antibiotics via an easily accessible, non-cytotoxic and orally bioavailable FtsZ inhibitor. / Lui, Hok Kiu; Gao, Wei; Cheung, Kwan Choi; Jin, Wen Bin; Sun, Ning; Kan, Jason W.Y.; Wong, Iris L.K.; Chiou, Jiachi; Lin, Dachuan; Chan, Edward W.C.; Leung, Yun-Chung; Chan, Tak Hang; Chen, Sheng; Chan, Kin-Fai; Wong, Kwok-Yin.

In: European Journal of Medicinal Chemistry, Vol. 163, 01.02.2019, p. 95-115.

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journal