Activity of a novel protonophore against methicillin-resistant Staphylococcus aureus

Nagendran Tharmalingam, Elamparithi Jayamani, Rajmohan Rajamuthiah, Dawilmer Castillo, Beth Burgwyn Fuchs, Michael J. Kelso, Eleftherios Mylonakis

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Aim: Compound 1-(4-chlorophenyl)-4,4,4-trifluoro-3-hydroxy-2-buten-1-one (compound 1) was identified as a hit against methicillin-resistant Staphylococcus aureus (MRSA) strain MW2. Methods & results: The MIC of compound 1 against MRSA was 4 μg/ml. The compound showed enhanced activity at acidic pH by lowering bacterial intracellular pH and exhibited no lysis of human red blood cells at up to 64 μg/ml and its IC50 against HepG2 cells was 32 μg/ml. The compound reduced 1-log10 colony forming units of intracellular MRSA in macrophages and prolonged the survival of MRSA-infected Caenorhabditis elegans (p = 0.0015) and Galleria mellonella (p = 0.0002). Conclusion: Compound 1 is a protonophore with potent in vitro and in vivo activity against MRSA and no toxicity in mammalian cells up to 8 μg/ml that warrants further investigation as a novel antibacterial.

Original languageEnglish (US)
Pages (from-to)1401-1411
Number of pages11
JournalFuture Medicinal Chemistry
Volume9
Issue number12
DOIs
StatePublished - Aug 2017

Keywords

  • Galleria mellonella
  • MRSA infection
  • S. aureus
  • antibiotic
  • macrophages
  • protonophore

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology
  • Drug Discovery

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