Soft QPCs: Biscationic Quaternary Phosphonium Compounds as Soft Antimicrobial Agents

• Type of Material: Article
• Authors: Samantha R Brayton, Villanova University; Zachary EA Toles, Villanova University; Christian A Sanchez, Emory University; Marina E Michaud, Emory University; Laura M Thierer, Villanova University; Taylor M Keller, University of Pennsylvania; Caitlin J Risener, Emory University; Cassandra Quave, Emory University; William Wuest, Emory University; Kevin PC Minbiole, Villanova University
• Language: English
• Date: 2023-03-16
• Publisher: AMER CHEMICAL SOC
• Publication Version: Final Published Version
• Copyright Statement: © 2023 The Authors. Published by American Chemical Society
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1021/acsinfecdis.2c00624943
• Title of Journal or Parent Work: ACS INFECTIOUS DISEASES
• Volume: 9
• Issue: 4
• Start Page: 943
• End Page: 951
• Grant/Funding Information: This work was funded by the National Institute of General Medical Sciences (R35 GM119426 to W.M.W.; T32 GM008602 to C.A.S.), the National Center for Complementary and Integrative Health (F31 AT011988 to C.J.R.), and Major Research Instrumentation grants from the National Science Foundation (CHE-1827930 and CHE-2018399 to K.P.C.M.).
• Keywords: INHIBITION; soft disinfectants; disinfectants; phosphorus; Science & Technology; Pharmacology & Pharmacy; Infectious Diseases; amphiphiles; QPCs; AMPHIPHILES; AMMONIUM-COMPOUNDS; Chemistry, Medicinal; Life Sciences & Biomedicine
• Research Categories: Chemistry, General

Abstract

Quaternary ammonium compounds (QACs) serve as a first line of defense against infectious pathogens. As resistance to QACs emerges in the environment, the development of next-generation disinfectants is of utmost priority for human health. Balancing antibacterial potency with environmental considerations is required to effectively counter the development of bacterial resistance. To address this challenge, a series of 14 novel biscationic quaternary phosphonium compounds (bisQPCs) have been prepared as amphiphilic disinfectants through straightforward, high-yielding alkylation reactions. These compounds feature decomposable or “soft” amide moieties in their side chains, anticipated to promote decomposition under environmental conditions. Strong bioactivity against a panel of seven bacterial pathogens was observed, highlighted by single-digit micromolar activity for compounds P6P-12A,12A and P3P-12A,12A. Hydrolysis experiments in pure water and in buffers of varying pH revealed surprising decomposition of the soft QPCs under basic conditions at the phosphonium center, leading to inactive phosphine oxide products; QPC stability (>24 h) was maintained in neutral solutions. The results of this work unveil soft QPCs as a potent and environmentally conscious new class of bisQPC disinfectants.