Bacterial resistance toward commonly employed biocides is a widespread yet underappreciated problem, one which needs not only a deeper understanding of the mechanisms by which resistance proliferates, but also strategies for mitigation. Bacteria utilize many methods, most notably efflux pumps, to circumvent the lytic capability of quaternary ammonium compounds (QACs).  However, currently used QAC antiseptics offer no means to address these modes of resistance. We recognized a polyaromatic structural motif analogous to structures that bind QacR, a negative transcriptional regulator of the efflux pump QacA, and envisioned a series of QACs based on this motif. Starting from commercially available dye scaffolds, we synthesized and evaluated the antimicrobial activity of 52 novel QACs bearing 1-3 quaternary ammonium centers. Striking differences in antimicrobial activity against bacteria bearing QAC resistance genes were observed, with up to a 125-fold increase in MIC for select structures against bacteria known to bear efflux pumps (i.e., MRSA). Trends in structure-resistance relationships are now more apparent. Additionally, we describe a previously overlooked trend regarding the intrinsic resistance of Gram-negative bacterial species.

Structure-Resistance Relationships: Interrogating Antiseptic Resistance in Bacteria Using Multicationic Quaternary Ammonium Dyes (multiQACs)

252nd National Meeting (2016)

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