Antimicrobial Action And Reversal Of Resistance In Mrsa By Difluorobenzamide Derivatives Targeted At Ftsz

• By: CHAI, Wern (University Of South Australia, Australia)
• Co-author(s): Dr Wern Chai (Health and Biomedical Innovation, Clinical and Health Sciences, University Of South Australia, Adelaide, Australia)
  Mr Jonathan Whittal (Health and Biomedical Innovation, Clinical and Health Sciences, University Of South Australia, Adelaide, Australia)
  Di Song (Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Shandong, P.R. China)
  Dr Steven Polyak (Health and Biomedical Innovation, Clinical and Health Sciences, University Of South Australia, Adelaide, Australia)
  Dr Abiodun Ogunniyi (Australian Centre for Antimicrobial Resistance Ecology, School of Animal and Veterinary Sciences, University of Adelaide, Adelaide, Australia)
  Yinhu Wang (Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Shandong, P.R. China / School of Pharmacy, Liocheng University, Shandong, P.R. China)
  Fanchao Bi (Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Shandong, P.R. China)
  Prof Shutao Ma (Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Shandong, P.R. China)
  Dr Susan Semple (Health and Biomedical Innovation, Clinical and Health Sciences, University Of South Australia, Adelaide, Australia / Quality Use of Medicines and Pharmacy Research Centre, Clinical and Health Sciences, University of South Australia, Adelaide, Australia)
  A/Prof Henrietta Venter (Health and Biomedical Innovation, Clinical and Health Sciences, University Of South Australia, Adelaide, Australia)
  
• Abstract:

  Background information
  The WHO recognizes antibiotic resistance as a top five global burden of disease. This threat necessitates urgent new therapies with novel mechanisms of action. In bacteria, the filamentous temperature sensitive Z-ring (FtsZ) protein represents an attractive target for the development of new antimicrobial agents as it plays a crucial role in cell division.
  
  Purpose
  This study sought to characterize the antimicrobial activity of five difluorobenzamide derivatives with non-heterocyclic substituents attached through the 3-oxygen.
  
  Method
  In this study, the difluorobenzamide derivatives of 3-methoxybenzamide were synthesized. Microscopic analysis was performed to determine if the derivatives inhibited bacterial cell division. On-target activities were assessed through their effects on the polymerization and GTPase activity of purified FtsZ. Reversal of resistance was tested in combination with beta-lactam antibiotics that are used in clinical practice. In silico docking was used to assess the compound binding site in vivo and in vitro toxicity using mammalian tubulin, liver cells and red blood cells were performed.
  
  Results
  The compounds displayed antimicrobial activity against the pathogenic bacterium methicillin resistant Staphylococcus aureus as well as clinically pathogenic MRSA strains. The compounds could act synergistically with beta-lactam antibiotics, suggesting there may be a potential for reversal of resistance. The compounds effectively inhibited cellular division as observed in the ‘ballooning’ phenotype and their ability to enhance GTPase activity and FtsZ polymerization in vivo. Additionally, off-target analysis was undertaken to ensure the compounds would not display haemolytic activity, cytotoxicity against mammalian cells and a nematode model in vitro.
  
  Conclusion
  This study identified promising new antimicrobial compounds that selectively inhibit bacterial cell division. It is also the first report of FtsZ-targeting compounds that could reverse the resistance of a beta-lactam antibiotic in clinically resistant MRSA. These derivatives are therefore promising compounds for further development as antimicrobial agents or as resistance breakers to re-sensitive MRSA to beta-lactam antibiotics.
  
  Topic area
  New medicines