New antimicrobial bioactivity against multidrugresistant gram-positive bacteria of kinase inhibitor imd0354

Iliana E. Escobar, Alexis White, Wooseong Kim, Eleftherios Mylonakis

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Multidrug-resistant pathogens pose a serious threat to human health. For decades, the antibiotic vancomycin has been a potent option when treating Gram-positive multidrug-resistant infections. Nonetheless, in recent decades, we have begun to see an increase in vancomycin-resistant bacteria. Here, we show that the nuclear factor-kappa B (NF-κB) inhibitor N-[3,5Bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (IMD0354) was identified as a positive hit through a Caenorhabditis elegans–methicillin-resistant Staphylococcus aureus (MRSA) infection screen. IMD0354 was a potent bacteriostatic drug capable of working at a minimal inhibitory concentration (MIC) as low as 0.06 µg/mL against various vancomycin-resistant strains. Interestingly, IMD0354 showed no hemolytic activity at concentrations as high as 16 µg/mL and is minimally toxic to C. elegans in vivo with 90% survival up to 64 µg/mL. In addition, we demonstrated that IMD0354′s mechanism of action at high concentrations is membrane permeabilization. Lastly, we found that IMD0354 is able to inhibit vancomycin-resistant Staphylococcus aureus (VRSA) initial cell attachment and biofilm formation at sub-MIC levels and above. Our work highlights that the NF-κB inhibitor IMD0354 has promising potential as a lead compound and an antimicrobial therapeutic candidate capable of combating multidrug-resistant bacteria.

Original languageEnglish
Article number665
Pages (from-to)1-17
Number of pages17
JournalAntibiotics
Volume9
Issue number10
DOIs
StatePublished - Oct 2020

Keywords

  • High-throughput screening
  • IMD0354
  • Vancomycin-resistant Staphylococcus aureus
  • Vancomycinresistant enterococci

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