Quaternary Phosphonium Compound Unveiled as a Potent Disinfectant against Highly Resistant Clinical Isolates.

is classified as a highest threat pathogen, urgently necessitating novel antimicrobials that evade resistance to combat its spread. Quaternary ammonium compounds (QACs) have afforded a valuable first line of defense against antimicrobial resistant pathogens as broad-spectrum amphiphilic disinfectant molecules. However, a paucity of innovation in this space has driven the emergence of QAC resistance. Through this work, we sought to identify next-generation disinfectant molecules with efficacy against highly resistant clinical isolates. We selected 12 best-in-class molecules from our previous investigations of quaternary ammonium and quaternary phosphonium compounds (QPCs) to test against a panel of 35 resistant clinical isolates. The results highlighted the efficacy of our next-generation compounds over leading commercial QACs, with our best-in-class QAC (2Pyr-11,11) and QPC (P6P-10,10) displaying improved activities with a few exceptions. Furthermore, we elucidated a correlation between colistin resistance and QAC resistance, wherein the only pan-resistant isolate of the panel, also harboring colistin resistance, exhibited resistance to all tested QACs. Notably, P6P-10,10 maintained efficacy against this strain with an IC of 3 μM. In addition, P6P-10,10 displayed minimum biofilm eradication concentrations as low as 32 μM against extensively drug resistant clinical isolates. Lastly, examining the development of disinfectant resistance and cross-resistance, we generated QAC-resistant mutants and observed the development of QAC cross-resistance. In contrast, neither disinfectant resistance nor cross-resistance was observed in under P6P-10,10 treatment. Taken together, the results of this work illustrate the need for novel disinfectant compounds to treat resistant pathogens, such as , and underscore the promise of QPCs, such as P6P-10,10, as viable next-generation disinfectant molecules.