Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic.
Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic; Department of Epidemiology, Faculty of Military Health Sciences, University of Defence in Brno, Trebesska 1575, 500 05, Hradec Kralove, Czech Republic.
Eur J Med Chem. 2020 Nov 15;206:112584. doi: 10.1016/j.ejmech.2020.112584. Epub 2020 Jul 19.
Quaternary ammonium salts (QASs) have been widely used for disinfection purposes because of their low price, high efficacy and low human toxicity for decades. However, precise mechanisms of action nor the powerful versatile agent against all antimicrobial species are known. In this study we have prepared 43 novel N-alkyl monoquaternary ammonium salts including 7 N,N-dialkyl monoquaternary ammonium salts differing bearing alkyl chain either of 12, 14 or 16 carbons. Together with 15 already published QASs we have studied the antimicrobial efficacy of all water-soluble compounds together with standard benzalkonium salts against Gram-positive (G+) and Gram-negative (G-) bacteria, anaerobic spore-forming Cl. difficile, yeasts, filamentous fungi and enveloped Varicella zoster virus (VZV). To address the mechanism of action, lipophilicity seems to be a key parameter which determines antimicrobial efficacy, however, exceptions are likely to occur and therefore QSAR analysis on the efficacy against G+ and G- bacteria was applied. We showed that antibacterial activity is higher when the molecule is larger, more lipophilic, less polar, and contains fewer oxygen atoms, fewer methyl groups bound to heteroatoms or fewer hydrogen atoms bound to polarized carbon atoms. In addition, from an application point of view, we have formulated mixtures, on the basis of obtained efficiency of individual compounds, in order to receive wide-spectrum agent. All formulated mixtures completely eradicated tested G+ and G- strains, including the multidrug-resistant P. aeruginosa as well as in case of yeasts. However, effect on A. fumigatus, Cl. difficile and VZV the exposition towards mixture resulted in significant reduction only. Finally, 3 out of 4 formulated mixtures were safer than reference commercial agent based on benzalkonium salts only in the skin irritation test using reconstructed human epidermidis.
季铵盐（QAS）因其价格低廉、高效、对人类毒性低，几十年来一直被广泛用于消毒目的。然而，其确切的作用机制以及对抗所有抗菌物种的强大多功能制剂尚不清楚。在这项研究中，我们制备了 43 种新型 N-烷基单季铵盐，其中包括 7 种不同的 N,N-二烷基单季铵盐，其烷基链分别为 12、14 或 16 个碳原子。结合 15 种已发表的 QAS，我们研究了所有水溶性化合物与标准苯扎氯铵盐对革兰氏阳性（G+）和革兰氏阴性（G-）细菌、厌氧芽孢形成的艰难梭菌、酵母、丝状真菌和包膜水痘带状疱疹病毒（VZV）的抗菌功效。为了阐明作用机制，亲脂性似乎是决定抗菌功效的关键参数，但可能会出现例外情况，因此对 G+和 G-细菌的功效进行了定量构效关系（QSAR）分析。我们表明，当分子较大、亲脂性更强、极性更小、含氧原子更少、与杂原子结合的甲基更少或与极化碳原子结合的氢原子更少时，抗菌活性更高。此外，从应用的角度来看，我们根据获得的单个化合物的效率来配制混合物，以获得广谱制剂。所有配制的混合物完全根除了测试的 G+和 G-菌株，包括多药耐药的铜绿假单胞菌，以及在酵母的情况下。然而，对 A. fumigatus、C. difficile 和 VZV 的影响，混合物的暴露仅导致显著减少。最后，在使用重建的人表皮进行皮肤刺激试验时，3 种配制的混合物中有 3 种比基于苯扎氯铵盐的参考商业制剂更安全。
