Drug repurposing: a dual-mechanism antibiotic combats MRSA and its high resistant phenotypes.

PURPOSE: Methicillin-resistant Staphylococcus aureus (MRSA) is frequently observed in biofilm form, exhibiting significant tolerance, particularly in the context of deep tissue infections such as osteomyelitis. This characteristic renders clinical treatment extremely challenging. Therefore, the development of novel antibacterial agents against MRSA and its biofilms is identified as an urgent priority.

METHODS

By drug repurposing, this study determines the antibacterial activity of the anti-amoebic small molecule tiliquinol against MRSA and its highly drug-resistant biofilms and evaluates its potential to induce MRSA resistance. The antibacterial mechanism of tiliquinol is examined utilizing transcriptomics, fluorescent probes, and quantitative reverse-transcription polymerase chain reaction. In addition, we evaluate in vivo antibacterial efficacy and safety profiles by established multiple murine infection models, including skin and soft tissue infection, sepsis, as well as the periprosthetic joint infection.

RESULTS

The research find that tiliquinol exhibits notable antibacterial activity against MRSA and its highly resistant biofilms avoiding resistance occurrence. Mechanism study reveals that the proton motive force and peptidoglycan are potential therapeutic targets by tiliquinol. Further, in various mouse infection models, favorable in vivo antibacterial efficacy with satisfied safety profiles of tiliquinol are confirmed.

CONCLUSION

Tiliquinol is recognized as a novel therapeutic strategy against refractory MRSA-related infections, particularly those associated with osteomyelitis and implant-related complications.