Tiliquinol, a Repurposed Anti-Amoebic, Combats MRSA and Its Highly Resistant Biofilms via Dual Mechanism

The escalating prevalence of Methicillin-resistant Staphylococcus aureus (MRSA), particularly in its biofilm form, poses a significant challenge in clinical settings. Biofilms exhibit high tolerance to conventional antibiotics, making deep tissue infections like osteomyelitis and periprosthetic joint infections (PJI) extremely difficult to treat. Current standard-of-care often falls short, leading to high morbidity and mortality rates. There is an urgent and unmet need for novel antibacterial agents that can effectively penetrate and eradicate MRSA biofilms while minimizing the risk of resistance development.

Researchers employed a drug repurposing strategy to evaluate the anti-amoebic small molecule tiliquinol for its antibacterial activity against MRSA and its highly drug-resistant biofilms. They assessed its potential to induce MRSA resistance over time. The antibacterial mechanism of tiliquinol was investigated using transcriptomics, fluorescent probes, and quantitative reverse-transcription polymerase chain reaction (qPCR). Furthermore, in vivo antibacterial efficacy and safety profiles were established using multiple murine infection models, including skin and soft tissue infection, sepsis, and periprosthetic joint infection.

Tiliquinol exhibited notable antibacterial activity against both planktonic MRSA and its highly resistant biofilms, crucially avoiding the occurrence of resistance. Mechanistic studies revealed that tiliquinol targets a dual pathway, disrupting both the proton motive force and peptidoglycan synthesis, identifying these as potential therapeutic targets. This dual mechanism likely contributes to its efficacy and low resistance potential. > In various mouse infection models, tiliquinol demonstrated favorable in vivo antibacterial efficacy with satisfied safety profiles, confirming its therapeutic potential in complex infection scenarios like periprosthetic joint infection.