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Antibacterial Properties of Four Novel Hit Compounds from a Methicillin-Resistant Staphylococcus aureus-Caenorhabditis elegans High-Throughput Screen

Journal Article


Abstract


  • There is an urgent need for the discovery of effective new antimicrobial agents to combat the rise of bacterial drug resistance. High-throughput screening (HTS) in whole-animal infection models is a powerful tool for identifying compounds that show antibacterial activity and low host toxicity. In this report, we characterize the activities of four novel antistaphylococcal compounds identified from an HTS campaign conducted using Caenorhabditis elegans nematodes infected with methicillin-resistant Staphylococcus aureus (MRSA). The hit compounds included an Nhydroxy

    indole—1, a substituted melamine derivative—2, N-substituted indolic alkyl isothiocyanate—3, and pdifluoromethylsulfide analog—4 of the well-known protonophore carbonyl cyanide m-chlorophenyl hydrazone. Minimal inhibitory concentrations (MICs) of the four compounds ranged from 2 to 8 μg/ml against MRSA-MW2 and Enterococcus faecium and all were bacteriostatic. The compounds were mostly inactive against Gram-negative pathogens, with only 1 and 4 showing slight activity (MIC= 32 μg/ml) against Acinetobacter baumanii. Compounds

    2 and 3 (but not 1 or 4) were found to perturb MRSA membranes. In phagocytosis assays, compounds 1, 2, and 4 inhibited the growth of internalized MRSA in macrophages, whereas compound 3 showed a remarkable ability to clear intracellular MRSA at its MIC ( p < 0.001). None of the compounds showed hemolytic activity at concentrations below 64 μg/ml ( p = 0.0021). Compounds 1, 2, and 4 (but not 3) showed synergistic activity against MRSA with ciprofloxacin, while compound 3 synergized with erythromycin, gentamicin, streptomycin, and vancomycin. In conclusion, we describe four new antistaphylococcal compounds that warrant further study as novel antibacterial agents against Gram-positive organisms.

Authors


  •   Tharmalingam, Nagendran (external author)
  •   Rajmuthiah, Rajmohan (external author)
  •   Kim, Wooseong (external author)
  •   Fuchs, Beth (external author)
  •   Jeyamani, Elamparithi (external author)
  •   Kelso, Michael J.
  •   Mylonakis, Eleftherios (external author)

Publication Date


  • 2018

Citation


  • Tharmalingam, N., Rajmuthiah, R., Kim, W., Fuchs, B. Burgwyn., Jeyamani, E., Kelso, M. J. & Mylonakis, E. (2018). Antibacterial Properties of Four Novel Hit Compounds from a Methicillin-Resistant Staphylococcus aureus-Caenorhabditis elegans High-Throughput Screen. Microbial Drug Resistance, 24 (5), 666-674.

Scopus Eid


  • 2-s2.0-85042733033

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/1416

Number Of Pages


  • 8

Start Page


  • 666

End Page


  • 674

Volume


  • 24

Issue


  • 5

Place Of Publication


  • United States

Abstract


  • There is an urgent need for the discovery of effective new antimicrobial agents to combat the rise of bacterial drug resistance. High-throughput screening (HTS) in whole-animal infection models is a powerful tool for identifying compounds that show antibacterial activity and low host toxicity. In this report, we characterize the activities of four novel antistaphylococcal compounds identified from an HTS campaign conducted using Caenorhabditis elegans nematodes infected with methicillin-resistant Staphylococcus aureus (MRSA). The hit compounds included an Nhydroxy

    indole—1, a substituted melamine derivative—2, N-substituted indolic alkyl isothiocyanate—3, and pdifluoromethylsulfide analog—4 of the well-known protonophore carbonyl cyanide m-chlorophenyl hydrazone. Minimal inhibitory concentrations (MICs) of the four compounds ranged from 2 to 8 μg/ml against MRSA-MW2 and Enterococcus faecium and all were bacteriostatic. The compounds were mostly inactive against Gram-negative pathogens, with only 1 and 4 showing slight activity (MIC= 32 μg/ml) against Acinetobacter baumanii. Compounds

    2 and 3 (but not 1 or 4) were found to perturb MRSA membranes. In phagocytosis assays, compounds 1, 2, and 4 inhibited the growth of internalized MRSA in macrophages, whereas compound 3 showed a remarkable ability to clear intracellular MRSA at its MIC ( p < 0.001). None of the compounds showed hemolytic activity at concentrations below 64 μg/ml ( p = 0.0021). Compounds 1, 2, and 4 (but not 3) showed synergistic activity against MRSA with ciprofloxacin, while compound 3 synergized with erythromycin, gentamicin, streptomycin, and vancomycin. In conclusion, we describe four new antistaphylococcal compounds that warrant further study as novel antibacterial agents against Gram-positive organisms.

Authors


  •   Tharmalingam, Nagendran (external author)
  •   Rajmuthiah, Rajmohan (external author)
  •   Kim, Wooseong (external author)
  •   Fuchs, Beth (external author)
  •   Jeyamani, Elamparithi (external author)
  •   Kelso, Michael J.
  •   Mylonakis, Eleftherios (external author)

Publication Date


  • 2018

Citation


  • Tharmalingam, N., Rajmuthiah, R., Kim, W., Fuchs, B. Burgwyn., Jeyamani, E., Kelso, M. J. & Mylonakis, E. (2018). Antibacterial Properties of Four Novel Hit Compounds from a Methicillin-Resistant Staphylococcus aureus-Caenorhabditis elegans High-Throughput Screen. Microbial Drug Resistance, 24 (5), 666-674.

Scopus Eid


  • 2-s2.0-85042733033

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/1416

Number Of Pages


  • 8

Start Page


  • 666

End Page


  • 674

Volume


  • 24

Issue


  • 5

Place Of Publication


  • United States