Quaternary Phosphonium Compounds: An Examination of Non-Nitrogenous Cationic Amphiphiles That Evade Disinfectant Resistance

Abstract

Quaternary ammonium compounds (QACs) serve as mainstays in the formulation of disinfectants and antiseptics. However, an over-reliance and misuse of our limited QAC arsenal has driven the development and spread of resistance to these compounds, as well as co-resistance to common antibiotics. Extensive use of these compounds throughout the COVID-19 pandemic thus raises concern for the accelerated proliferation of antimicrobial resistance and demands for next-generation antimicrobials with divergent architectures that may evade resistance. To this end, we endeavored to expand beyond canonical ammonium scaffolds and examine quaternary phosphonium compounds (QPCs). Accordingly, a synthetic and biological investigation into a library of novel QPCs unveiled biscationic QPCs to be effective antimicrobial scaffolds with improved broad-spectrum activities compared to commercial QACs. Notably, a subset of these compounds was found to be less effective against a known QAC-resistant strain of MRSA. Bioinformatic analysis revealed the unique presence of a family of small multiresistant transporter proteins, hypothesized to enable efflux-mediated resistance to QACs and QPCs. Further investigation of this resistance mechanism through efflux-pump inhibition and membrane depolarization assays illustrated the superior ability of P6P-10,10 to perturb the cell membrane and exert the observed broad-spectrum potency compared to its commercial counterparts. Collectively, this work highlights the promise of biscationic phosphonium compounds as next-generation disinfectant molecules with potent bioactivities, thereby laying the foundation for future studies into the synthesis and biological investigation of this nascent antimicrobial class.

Rigidity‐Activity Relationships of bisQPC Scaffolds against Pathogenic Bacteria

“…This was circumvented by exposure to the desired alkyl bromide, which led to clean monoalkylation, followed by methylation with iodomethane to produce the corresponding bisQPC structures; this was accomplished for three compounds (Scheme 1C). Inspection of 31 P, 13 C, and 1 H NMR spectra of these P-2Z-P derived compounds indicated that the resulting products had isomerized to the E-alkenes; all 31 P resonances were observed at precisely 23.8 ppm, matching the P-2E-P derived bisQPCs. This isomerization would seemingly minimize the significant steric strain imposed by the four phenyl groups.…”

“…All yields refer to spectroscopically pure compounds. 1 H, 13 C, and 31 P NMR spectra were measured with a 400 MHz or 500 MHz JEOL spectrophotometer, and chemical shifts were reported on a δ-scale (ppm) downfield from TMS or 85 % H 3 PO 4 . Coupling constants were calculated in Hertz.…”

“…Coupling constants were calculated in Hertz. The solvent used was chloroform-d (CDCl 3 ), with an internal reference of 7.26 ppm for 1 H NMR and 77.16 ppm for 13 C NMR. Accurate mass spectrometry data was acquired on an AB Sciex 5600 TripleTOF using electrospray ionization in positive mode.…”

“…[6] Our research groups have spent a decade on the construction of over 700 novel cationic disinfectant structures, endeavoring to identify structure-activity relationships (SAR) that can guide the development of novel, safe, and effective antimicrobials. [7][8] Recently, to broaden the structural variety of amphiphilic antiseptics more significantly, we expanded our interests to the production of trivalent sulfonium compounds (TSCs) [9][10][11][12] and to quaternary phosphonium compounds (QPCs), [13][14][15][16][17] hypothesizing that expanding beyond positively charged nitrogen species would afford novelty to challenge bacterial resistance mechanisms. [18] A recent publication from our groups reported that select QPC structures demonstrate significant broad-spectrum antimicrobial activity, and in some circumstances, surpass some of the most potent commercial QAC compounds while showing no capitulation to bacterial resistance mechanisms.…”

“…[18] A recent publication from our groups reported that select QPC structures demonstrate significant broad-spectrum antimicrobial activity, and in some circumstances, surpass some of the most potent commercial QAC compounds while showing no capitulation to bacterial resistance mechanisms. [13] For example, P6P-10,10 is a biscationic structure (bisQPC) with a simple 1-step synthesis and single-digit micromolar MIC values against a panel of bacteria bearing QAC-resistance mechanisms.…”