Bushy-Tailed QACs: The development of multicationic quaternary ammonium compounds with a high degree of alkyl chain substitution.

Quaternary ammonium compounds have served as a first line of protection for human health as surface disinfectants and sanitizers for nearly a century. However, increasing levels of bacterial resistance have spurred the development of novel QAC architectures. In light of the observed reduction in eukaryotic cell toxicity when the alkyl chains on QACs are shorter in nature (≤10C), we prepared 47 QAC architectures that bear multiple short alkyl chains appended to up to three cationic groups, thus rendering them "bushy-tailed" multiQACs. Antibacterial activity was strong (often ~1-4 µM) in a varied set of bushy-tailed architectures, though observed therapeutic indices were not significantly improved over QAC structures bearing fewer and longer alkyl chains.

Exploring the Correlation of Dynamic Surface Tension with Antimicrobial Activities of Quaternary Ammonium-Based Disinfectants.

Quaternary ammonium compound (QAC) disinfectants represent one of our first lines of defense against pathogens. Their inhibitory and bactericidal activities are usually tested through minimum inhibitory concentration (MIC) and time-kill assays, but these assays can become cumbersome when screening many compounds. We investigated how the dynamic surface tension (DST) measurements of QACs correlate with these antimicrobial activities by testing a panel of potent and structurally varied QACs against the gram-positive Staphylococcus aureus and the gram-negative Pseudomonas aeruginosa. We found that DST values correlated well with bactericidal activity in real-world disinfection conditions but not with MIC values. Moreover, no correlation between these two antimicrobial activities of QACs (bactericidal and inhibition) was observed. In addition, we observed that the bactericidal activity of our QAC panel against the gram-negative P. aeruginosa was severely affected in the presence of hard water. Interestingly, we found that the counterion of the QAC affects the killing of bacteria in these conditions, a phenomenon not observed in most MIC assessments. Moreover, some of our best-in-class QACs show enhanced bactericidal activity when combined with a commercially available QAC. In conclusion, we determined that an intrinsic physical property of QACs (DST) can be used as a technique to screen for bactericidal activity of QACs in conditions that mimic real-world disinfection conditions.

Chimeric Amphiphilic Disinfectants: Quaternary Ammonium/Quaternary Phosphonium Hybrid Structures.

Cationic biocides play a crucial role in the disinfection of domestic and healthcare surfaces. Due to the rise of bacterial resistance towards common cationic disinfectants like quaternary ammonium compounds (QACs), the development of novel actives is necessary for effective infection prevention and control. Toward this end, a series of 15 chimeric biscationic amphiphilic compounds, bearing both ammonium and phosphonium residues, were prepared to probe the structure and efficacy of mixed cationic ammonium-phosphonium structures. Compounds were obtained in two steps and good yields, with straightforward and chromatography-free purifications. Antibacterial activity evaluation of these compounds against a panel of seven bacterial strains, including two MRSA strains as well as opportunistic pathogen A. baumannii, were encouraging, as low micromolar inhibitory activity was observed for multiple structures. Alkyl chain length on the ammonium group was, as expected, a major determinant of bioactivity. In addition, high therapeutic indexes (up to 125-fold) for triphenyl phosphonium-bearing amphiphiles were observed when comparing antimicrobial activity to mammalian cell lysis activity.

Soft QPCs: Biscationic Quaternary Phosphonium Compounds as Soft Antimicrobial Agents.

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.

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

Quaternary ammonium compounds (QACs) are vital disinfectants for the neutralization of pathogenic bacteria in clinical, domestic, and commercial settings. After decades of dependence on QACs, the emergence of antimicrobial resistance to this class of compounds threatens the ability of existing QAC products to effectively manage rising bacterial threats. The need for new disinfectants is therefore urgent, with quaternary phosphonium compounds (QPCs) emerging as a new class of promising antimicrobials that boast significant activity against highly resistant bacteria. Reported here is a series of twenty-one novel QPCs that replace phenyl substituents on the phosphorus center with alkyl groups yet allow for rapid synthetic routes in high yields. Within this series are structures containing methyl, ethyl, or cyclohexyl phosphonium substituents on bisphosphane scaffolds bearing ethyl linkers, affording atom economical structures and ones that represent exact analogs to nitrogenous amphiphiles. The resultant bisQPC structures display high antibacterial efficacy enjoyed by comparably constructed QACs, with three structures in the single-digit micromolar activity range despite structural simplification.

Double BAC and Triple BAC: A Systematic Analysis of the Disinfectant Properties of Multicationic Derivatives of Benzalkonium Chloride (BAC).

Over the past decades, the shortcomings of established quaternary ammonium disinfectants have become increasingly clear. Although benzalkonium chloride (BAC) has enjoyed nearly a century of significantly protecting human health through surgical preparation, home use, and industrial applications, increasing levels of bacterial resistance have rendered it decreasingly effective. In light of more recent efforts that have informed us that multicationic amphiphilic disinfectants show both higher activity as well as diminished susceptibility to resistance, we embarked on the preparation of 27 multicationic QACs in an attempt to clearly document structure-activity relationships of next-generation BAC structures. Select biscationic BAC derivatives demonstrate single-digit micromolar activity against all seven bacteria tested and MIC values of 2- to 32-fold better than BAC. Particularly notable is the improvement against the more concerning bacteria like Acinetobacter baumannii and Pseudomonas aeruginosa, which pose a modern threat to legacy disinfectants like BAC. With simple synthetic paths, consistently high yields (averaging ∼80 %), and strong biological activity, potent structures with clear SAR trends and strong therapeutic indices have been established.

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

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.

Rigidity-Activity Relationships of bisQPC Scaffolds against Pathogenic Bacteria.

Biscationic quaternary phosphonium compounds (bisQPCs) represent a promising class of antimicrobials, displaying potent activity against both Gram-negative and Gram-positive bacteria. In this study, we explored the effects of structural rigidity on the antimicrobial activity of QPC structures bearing a two-carbon linker between phosphonium groups, testing against a panel of six bacteria, including multiple strains harboring known disinfectant resistance mechanisms. Using simple alkylation reactions, 21 novel compounds were prepared, although alkene isomerization as well as an alkyne reduction were observed during the respective syntheses. The resulting bisQPC compounds showed strong biological activity, but were hampered by diminished solubility of their iodide salts. One compound (P2P-10,10 I) showed single-digit micromolar activity against the entire panel of bacteria. Overall, intriguing biological activity was observed, with less rigid structures displaying better efficacy against Gram-negative strains and more rigid structures demonstrating slightly increased efficacy against S. aureus strains.