Quaternary Phosphonium Compounds: An Examination of Non-Nitrogenous Cationic Amphiphiles That Evade Disinfectant Resistance.
ACS Infect Dis
; 8(2): 387-397, 2022 02 11.
Article
em En
| MEDLINE
| ID: mdl-35077149
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.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Desinfetantes
/
COVID-19
Limite:
Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article