Synergistic and Additive Effects of Menadione in Combination with Antibiotics on Multidrug‐Resistant Staphylococcus aureus: Insights from Structure‐Function Analysis of Naphthoquinones

Abstract

Antimicrobial resistance (AMR) has interfered with effective treatment of microbial infection and increased the risk of microbial spread, illness, and deaths. The synergistic activities of combinations of antimicrobials offer satisfactory approaches to some extent. Structurally diverse naphthoquinones (NQs) including menadione (‐CH3 at C‐2) exhibit substantial antimicrobial activities against multidrug‐resistant (MDR) pathogens. We explored the combinations of menadione with antibiotic ciprofloxacin or ampicillin against Staphylococcus aureus and its biofilms. We found an additive (0.5 < FICI ≤ 1.0) and synergistic (FICI ≤ 0.5) effect of menadione with ciprofloxacin and ampicillin, respectively. High reactive oxygen species (ROS) activity and inhibition of biofilm formation (>90%) were also seen. However, preformed biofilms were not affected. Dent formation was also evident in S. aureus treated with the test compounds. The structure‐function relationship (SFR) of NQs was used to determine and predict their activity pattern against pathogens. Analysis of 10 structurally distinct NQs revealed that the compounds with ‐Cl, ‐Br, ‐CH3, or ‐OH groups displayed the lowest MICs (32–256 µg/mL). Furthermore, 1,4‐NQs possessing a halogen or ‐CH3 moiety showed elevated ROS activity, whereas molecules with an ‐OH group affected the cell integrity. Improved activity of antimicrobial combinations and SFR approaches are significant in antimicrobial therapies.

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