Quaternary Phosphonium Compound Unveiled as a Potent Disinfectant against Highly Resistant Acinetobacter baumannii Clinical Isolates

Abstract

Acinetobacter baumannii is classified as a highest threat pathogen, urgently necessitating novel antimicrobials that evade resistance to combat its spread. Quaternary ammonium compounds (QACs) have afforded a valuable first line of defense against antimicrobial resistant pathogens as broad-spectrum amphiphilic disinfectant molecules. However, a paucity of innovation in this space has driven the emergence of QAC resistance. Through this work, we sought to identify next-generation disinfectant molecules with efficacy against highly resistant A. baumannii clinical isolates. We selected 12 best-in-class molecules from our previous investigations of quaternary ammonium and quaternary phosphonium compounds (QPCs) to test against a panel of 35 resistant A. baumannii clinical isolates. The results highlighted the efficacy of our next-generation compounds over leading commercial QACs, with our best-in-class QAC (2Pyr-11,11) and QPC (P6P-10,10) displaying improved activities with a few exceptions. Furthermore, we elucidated a correlation between colistin resistance and QAC resistance, wherein the only pan-resistant isolate of the panel, also harboring colistin resistance, exhibited resistance to all tested QACs. Notably, P6P-10,10 maintained efficacy against this strain with an IC90 of 3 μM. In addition, P6P-10,10 displayed minimum biofilm eradication concentrations as low as 32 μM against extensively drug resistant clinical isolates. Lastly, examining the development of disinfectant resistance and cross-resistance, we generated QAC-resistant A. baumannii mutants and observed the development of QAC cross-resistance. In contrast, neither disinfectant resistance nor cross-resistance was observed in A. baumannii under P6P-10,10 treatment. Taken together, the results of this work illustrate the need for novel disinfectant compounds to treat resistant pathogens, such as A. baumannii, and underscore the promise of QPCs, such as P6P-10,10, as viable next-generation disinfectant molecules.

Dissemination of Clinical Acinetobacter baumannii Isolate to Hospital Environment during the COVID-19 Pandemic

“…Here, special attention should be given to the resistance of A. baumannii biofilms to commercial disinfectants [ 16 ]. The need for the identification of novel disinfectant compounds to treat resistant pathogens, such as A. baumannii , has been recognized and emphasized [ 31 , 32 ].…”

Atom Economical QPCs: Phenyl-Free Biscationic Quaternary Phosphonium Compounds as Potent Disinfectants

“…For approximately 100 years, quaternary ammonium compounds (QACs) have been employed as successful tools to mitigate the transfer of pathogenic bacteria. , Over much of this time, society has heavily relied on just a handful of these disinfecting amphiphilic compounds, with the most visible commercial disinfectant of this class being benzalkonium chloride (BAC), a mixture of long-chained alkyl dimethylbenzylammonium chlorides. − While mainstay disinfectants such as BAC have proven highly valuable for decades, they are now showing vulnerabilities as bacteria continue to evolve antimicrobial resistance mechanisms . Notable pathogens such as A. baumannii and P. aeruginosa have developed sufficient resistance mechanisms toward common disinfectants that they are renewing the problem of bacterial infections in hospital, domestic, and commercial settings. − In order to combat the growing problem of antimicrobial resistance (AMR), ongoing efforts toward the synthesis and antimicrobial evaluation of novel QACs are underway . Along these lines, our groups have systematically evaluated a variety of QAC structural motifs to identify molecular features that can inform the rational design of new classes of disinfectants; we have recently advanced to machine learning techniques to predict the bioactivity of proposed compounds .…”

“… This structure took advantage of the ready availability and stability of phenyl-substituted bisphosphines, which are often employed as ligands for catalysis; presumably, the phenyl substituents stabilize the phosphines and inhibit oxidation and other reactivity. The high degree of antimicrobial efficacy observed with Ph P6P-10,10 toward both Gram-positive and Gram-negative pathogens, including highly resistant pathogenic bacteria, was unprecedented when compared with 14 antibiotics and 15 other disinfectant amphiphiles. , …”

“…The high degree of antimicrobial efficacy observed with Ph P6P-10,10 toward both Gram-positive and Gram-negative pathogens, including highly resistant pathogenic bacteria, was unprecedented when compared with 14 antibiotics and 15 other disinfectant amphiphiles. 10,15 Given the promise of this early generation of bisQPC disinfectants, new alternatives are desired to expand this emerging class of amphiphiles. We envisioned an opportunity to accomplish two parallel goals, aiming (1) to determine if the bulky phenyl groups could be replaced with smaller alkyl groups, rendering the disinfectant structures more atom economical, and (2) to prepare exact nitrogen-and phosphorus-bearing analogs in amphiphilic disinfectants, thus scrutinizing the role of the cationic element in the antimicrobial action.…”

“… 5 Notable pathogens such as A. baumannii and P. aeruginosa have developed sufficient resistance mechanisms toward common disinfectants that they are renewing the problem of bacterial infections in hospital, domestic, and commercial settings. 6 − 10 In order to combat the growing problem of antimicrobial resistance (AMR), ongoing efforts toward the synthesis and antimicrobial evaluation of novel QACs are underway. 11 Along these lines, our groups have systematically evaluated a variety of QAC structural motifs to identify molecular features that can inform the rational design of new classes of disinfectants; we have recently advanced to machine learning techniques to predict the bioactivity of proposed compounds.…”