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

doi:10.1016/j.ejmech.2018.11.052

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

Eur J Med Chem. 2019 Feb 1:163:95-115. doi: 10.1016/j.ejmech.2018.11.052. Epub 2018 Nov 24.

Authors

Affiliations

¹ State Key Laboratory of Chemical Biology and Drug Discovery and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, China.
² Shenzhen Key Laboratory for Food Biological Safety Control, Food Safety and Technology Research Centre, The Hong Kong PolyU Shenzhen Research Institute, Shenzhen, China.
³ State Key Laboratory of Chemical Biology and Drug Discovery and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, China; Department of Chemistry, McGill University, Montreal, Quebec, H3A 2K6, Canada.
⁴ State Key Laboratory of Chemical Biology and Drug Discovery and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, China; Shenzhen Key Laboratory for Food Biological Safety Control, Food Safety and Technology Research Centre, The Hong Kong PolyU Shenzhen Research Institute, Shenzhen, China.
⁵ State Key Laboratory of Chemical Biology and Drug Discovery and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, China. Electronic address: kf.chan@polyu.edu.hk.
⁶ State Key Laboratory of Chemical Biology and Drug Discovery and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, China. Electronic address: kwok-yin.wong@polyu.edu.hk.

PMID: 30503946
DOI: 10.1016/j.ejmech.2018.11.052

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.

Keywords: 3-Aminobenzamides; FtsZ inhibitor; Methicillin-resistant Staphylococcus aureus; β-Lactam antibiotics.

MeSH terms

Animals
Bacterial Proteins / antagonists & inhibitors*
Binding Sites
Cefuroxime / therapeutic use
Cytoskeletal Proteins / antagonists & inhibitors*
Drug Synergism
Methicillin-Resistant Staphylococcus aureus / drug effects*
Mice
Small Molecule Libraries
Staphylococcal Infections / drug therapy
Staphylococcus aureus
beta-Lactams / therapeutic use*

Substances

Bacterial Proteins
Cytoskeletal Proteins
FtsZ protein, Bacteria
Small Molecule Libraries
beta-Lactams
Cefuroxime