Bioorganic Investigation of Multicationic Antimicrobials to Combat QAC-Resistant Staphylococcus aureus

Quaternary ammonium compounds (QACs) have historically served as a first line of defense against pathogenic bacteria. Recent reports have shown that QAC resistance is increasing at an alarming rate, especially among methicillin-resistant Staphylococcus aureus (MRSA), and preliminary work has suggested that the number of cations present in the QAC scaffold inversely correlates with resistance. Given our interest in multiQACs, we initiated a multipronged approach to investigate their biofilm eradication properties, antimicrobial activity, and the propensity of methicillin-susceptible S. aureus (MSSA) to develop resistance toward these compounds. Through these efforts we identified multiQACs with superior profiles against resistant (MRSA) planktonic bacteria and biofilms. Furthermore, we document the ability of MSSA to develop resistance to several commercial monoQAC disinfectants and a novel aryl bisQAC, yet we observe no resistance to multiQACs. This work provides insight into the mechanism and rate of resistance development of MSSA and MRSA toward a range of QAC structures.