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

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, Sheng Chen, Kin Fai Chan, Kwok Yin Wong

Research output: Journal article publicationJournal articleAcademic researchpeer-review

14 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)95-115
Number of pages21
JournalEuropean Journal of Medicinal Chemistry
Volume163
DOIs
Publication statusPublished - 1 Feb 2019

Keywords

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

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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