| Summary: | The emergence of drug-resistant <i>Staphylococcus aureus</i> is responsible for high morbidity and mortality worldwide. New therapeutic options are needed to fight the increasing antimicrobial resistance among <i>S. aureus</i> in the clinical setting. We, therefore, characterized the in silico absorption, distribution, metabolism, elimination, and toxicity (ADMET) and in vitro antimicrobial activity of 5-nitro-2-thiophenecarbaldehyde N-((E)-(5-nitrothienyl)methylidene)hydrazone (KTU-286) against drug-resistant <i>S. aureus</i> strains with genetically defined resistance mechanisms. The antimicrobial activity of KTU-286 was determined by CLSI recommendations. The ADMET properties were estimated by using in silico modeling. The activity on biofilm integrity was examined by crystal violet assay. KTU-286 demonstrated low estimated toxicity and low skin permeability. The highest antimicrobial activity was observed among pan-susceptible (Pan-S) <i>S. aureus</i> (minimal inhibitory concentration (MIC) 0.5–2.0 µg/mL, IC<sub>50</sub> = 0.460 µg/mL), followed by vancomycin resistant <i>S. aureus</i> (VRSA) (MIC 4.0 µg/mL, IC<sub>50</sub> = 1.697 µg/mL) and methicillin-resistant <i>S. aureus</i> (MRSA) (MIC 1.0–16.0 µg/mL, IC<sub>50</sub> = 2.282 µg/mL). KTU-286 resulted in significant (<i>p</i> < 0.05) loss of <i>S. aureus</i> biofilm integrity in vitro. Further studies are needed for a better understanding of safety, synergistic relationship, and therapeutic potency of KTU-286.
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