The Development of Novel Disinfectants to Overcome Bacterial Resistance

Project Summary Bacterial infections cause a tremendous burden to human health, and our first line of defense – amphiphilic disinfectants and antiseptics – rely on century-old technology and are now susceptible to bacterial resistance. This research program has worked for over a decade to develop novel disinfectants, broadly expanding

beyond the dogmatic reliance on single-cation amphiphiles like benzalkonium chloride. We aim to capitalize on recent insights, and forge innovations as yet unseen by bacteria. Specifically, we will continue to explore phosphorus-based analogues to traditional disinfectants (quaternary phosphonium compounds or QPCs);

work to improve atom economy and mitigate toxicity via innovative structure design; endeavor to better understand how a cationic center (whatever the element) influences bioactivity; and finally broaden our understanding of structure-activity relationships, anchored by specific knowledge of charge density and

solution behaviors. While our group has prepared roughly 840 novel disinfectant compounds to date, of first priority will be the construction of an even wider variety of amphiphilic structures. This will take advantage of our recent discoveries in multicationic QPC structure classes, which show the ability to eradicate bacterial strains that

have otherwise been deemed pan-resistant. Compounds with bushy-tails – species bearing multiple mid- length alkyl chains – as well as chimeric phosphonium/ammonium hybrids and less-explored bolaamphiphilic structures will be pursued to broaden out structure-activity relationship understanding. We also aim to better understand how the electronic nature of our cationic atom (P vs N) in our

amphiphiles can correlate to, and ultimately predict, bioactivity. Charge density analyses (aided by x-ray structure analysis in the lab of Michael Zdilla at Temple University) and Hammett-style electron density- vs-bioactivity plots will enhance our fundamental understanding of how cationic character influences

antimicrobial activity and resistance susceptibility. Dynamic surface tension behavior data will be correlated to time-kill observations to further expand the utility of these disinfectants. At the forefront of this research program is the work of undergraduate collaborators, who have been the drivers of our 36 publications in this field, and serve as first authors on 10 of our papers. We envision

continuing to employ straightforward chemical syntheses, based on hypothesis-driven rationales. The result is twofold: we are able to learn a great deal about the antibacterial activity of QPC and QAC scaffolds with evaluations of individual structural motifs in a very short period of time, and our students are able to

experience interdisciplinary science, as part of a collaborative, multidisciplinary team to advance our knowledge.