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

doi:10.4155/fmc-2017-0047

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

Houston Methodist

Research output: Contribution to journal › Article › peer-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 language	English (US)
Pages (from-to)	1401-1411
Number of pages	11
Journal	Future Medicinal Chemistry
Volume	9
Issue number	12
DOIs	https://doi.org/10.4155/fmc-2017-0047
State	Published - Aug 2017

Keywords

antibiotic
Galleria mellonella
macrophages
MRSA infection
protonophore
S. aureus

ASJC Scopus subject areas

Molecular Medicine
Pharmacology
Drug Discovery

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10.4155/fmc-2017-0047

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title = "Activity of a novel protonophore against methicillin-resistant Staphylococcus aureus",

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.",

keywords = "antibiotic, Galleria mellonella, macrophages, MRSA infection, protonophore, S. aureus",

author = "Nagendran Tharmalingam and Elamparithi Jayamani and Rajmohan Rajamuthiah and Dawilmer Castillo and Fuchs, {Beth Burgwyn} and Kelso, {Michael J.} and Eleftherios Mylonakis",

note = "Publisher Copyright: {\textcopyright} 2017 Future Science Ltd.",

year = "2017",

month = aug,

doi = "10.4155/fmc-2017-0047",

language = "English (US)",

volume = "9",

pages = "1401--1411",

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T1 - Activity of a novel protonophore against methicillin-resistant Staphylococcus aureus

AU - Tharmalingam, Nagendran

AU - Jayamani, Elamparithi

AU - Rajamuthiah, Rajmohan

AU - Castillo, Dawilmer

AU - Fuchs, Beth Burgwyn

AU - Kelso, Michael J.

AU - Mylonakis, Eleftherios

PY - 2017/8

Y1 - 2017/8

N2 - 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.

AB - 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.

KW - antibiotic

KW - Galleria mellonella

KW - macrophages

KW - MRSA infection

KW - protonophore

KW - S. aureus

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Activity of a novel protonophore against methicillin-resistant Staphylococcus aureus

Abstract

Keywords

ASJC Scopus subject areas

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