Activity of a novel protonophore against methicillin-resistant Staphylococcus aureus

Authors

Nagendran Tharmalingam, Brown University
Elamparithi Jayamani, Brown University, Massachusetts General Hospital
Rajmohan Rajamuthiah, Brown University
Dawilmer Castillo, Brown University
Beth Fuchs, Brown University
Michael J. Kelso, University of WollongongFollow
Eleftherios Mylonakis, Brown University

RIS ID

115987

Publication Details

Tharmalingam, N., Jayamani, E., Rajamuthiah, R., Castillo, D., Fuchs, B. Burgwyn., Kelso, M. J. & Mylonakis, E. (2017). Activity of a novel protonophore against methicillin-resistant Staphylococcus aureus. Future Medicinal Chemistry, 9 (12), 1401-1411.

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.