Evaluation of lawsone as a potential inhibitor of Staphylococcus aureus efflux pump mediated drugs resistance: An in-vitro and in-silico study.

Staphylococcus aureus (S. aureus) is a causative agent of a wide range of infections such as staphylococcal scalded skin syndrome, toxic shock syndrome, necrotizing pneumonia, endocarditis, and osteomyelitis, posing a significant challenge in clinical management. This study explores the antibacterial potential of lawsone on S. aureus using experimental and computational methods. The minimum inhibitory concentration (MIC) of lawsone (alone and in combination with erythromycin, tetracycline, norfloxacin and ciprofloxacin) on 8 clinical multi-drug resistant S. aureus was evaluated in vitro. The ability of lawsone to modulate antibiotic susceptibility was also determined. Molecular docking was carried out to investigate the binding affinities between lawsone and five efflux pumps (EPP) (NorA, NorB, MsrA, SepA, and MefA) and a ribosomal protection protein (TetM) implicated in S. aureus drug resistance. Furthermore, molecular dynamics simulations (MDS) were performed to assess the stability of the protein-ligand complexes throughout the 100 ns simulation period. In addition, the physicochemical properties, drug-likeness, and toxicity of the lawsone were predicted. Lawsone showed synergistic effects with erythromycin, tetracycline, norfloxacin, and ciprofloxacin, as indicated by the modulation factors (MF) ranging from 2 to > 16. Notably, the strain SA383 showed MF values of > 8 for two antibiotics (ciprofloxacin and erythromycin), and > 16 for norfloxacin. Molecular docking revealed strong binding affinities between lawsone and the evaluated S. aureus drug resistant proteins. The MDS confirmed the stability of the lawsone-protein complexes over 100 ns simulation period, supporting its potential as an efflux pump inhibitor (EPI). ADMET profiling of lawsone demonstrated favorable drug-likeness, pharmacokinetics, and low toxicity. Lawsone does not inhibit major cytochrome P450 enzymes. Toxicity predictions also showed no significant risks of carcinogenicity or immunotoxicity, but potential mutagenicity and nephrotoxicity which require further study. Lawsone also exhibits no predicted activity on androgen receptors, aromatase, or GABA receptors, indicating minimal hormonal disruption. These findings highlight lawsone as a promising candidate for the development of a new EPI candidate, particularly against antibiotic-resistant S. aureus.