Antimicrobial Action and Reversal of Resistance in MRSA by Difluorobenzamide Derivatives Targeted at FtsZ.

Wern Chern Chai,Fangchao Bi,Abiodun D Ogunniyi,Susan J Semple,Di Song,Shutao Ma,Steven W Polyak,Jonathan J Whittall,Henrietta Venter,Yinhu Wang

doi:10.3390/antibiotics9120873

Abstract

The bacterial cell division protein, FtsZ, has been identified as a target for antimicrobial development. Derivatives of 3-methoxybenzamide have shown promising activities as FtsZ inhibitors in Gram-positive bacteria. We sought to characterise the activity of five difluorobenzamide derivatives with non-heterocyclic substituents attached through the 3-oxygen. These compounds exhibited antimicrobial activity against methicillin resistant Staphylococcus aureus (MRSA), with an isopentyloxy-substituted compound showing modest activity against vancomycin resistant Enterococcus faecium (VRE). The compounds were able to reverse resistance to oxacillin in highly resistant clinical MRSA strains at concentrations far below their MICs. Three of the compounds inhibited an Escherichia coli strain lacking the AcrAB components of a drug efflux pump, which suggests the lack of Gram-negative activity can partly be attributed to efflux. The compounds inhibited cell division by targeting S. aureus FtsZ, producing a dose-dependent increase in GTPase rate which increased the rate of FtsZ polymerization and stabilized the FtsZ polymers. These compounds did not affect the polymerization of mammalian tubulin and did not display haemolytic activity or cytotoxicity. These derivatives are therefore promising compounds for further development as antimicrobial agents or as resistance breakers to re-sensitive MRSA to beta-lactam antibiotics.

Highlights

Antimicrobial resistance is a major healthcare issue with multidrug resistant organisms such as methicillin resistant Staphylococcus aureus (MRSA) being a particular concern [1,2]
We have previously reported on the synthesis and antimicrobial activity of a series of 3current study, five compounds (1–5) were selected based on their promising antimicrobial activity methoxybenzamide derivatives based on the 2,6-difluorobenzamide pharmacophore [23,24]
For the against β-lactamase producing S. aureus [28]. These compounds were further current study, five compounds (1–5) were selected based on their promising antimicrobial activity screened for antimicrobial activity against an extended panel of Gram-positive

Summary

Introduction

Antimicrobial resistance is a major healthcare issue with multidrug resistant organisms such as methicillin resistant Staphylococcus aureus (MRSA) being a particular concern [1,2]. One of the five objectives of this multifaceted plan is to increase the investment in development of new antimicrobials with novel mechanisms of action. One potential drug target for new antimicrobials is the bacterial cell division protein known as filamentous temperature sensitive Z-ring (FtsZ) protein. This protein represents an attractive target for development of novel antimicrobial agents, as it plays an essential role in bacterial cell division in both Gram-positive and Gram-negative bacteria [4] and is unique to bacteria. Monomers of FtsZ polymerize into filaments at the division site in the presence of GTP that is hydrolysed to GDP. These protofilaments come together through a process described as treadmilling [5]

Methods

Results

Conclusion