Department of Chemistry, University of Montréal, Faculté des Arts et des Sciences, 2900 Edouard Montpetit, CP 6128 succursalle centre ville, Montréal, QC, H3C 3J7, Canada.
ChemMedChem. 2018 Dec 6;13(23):2567-2572. doi: 10.1002/cmdc.201800639. Epub 2018 Nov 19.
The increased prevalence of antibiotic-resistant bacteria is a critical issue for human health. Developing new antibiotic agents is vital for fighting persistent infections and lowering mortality rates. In this study, we designed lutidine-disubstituted bis-benzimidazolium salts (lutidine-bis-benzimidazolium core with octyl, adamantyl, and cholesteryl lipophilic side chains), and tested their antimicrobial activity, their capacity to inhibit planktonic bacterial and fungal growth, and their ability to inhibit the formation of or disrupt mature methicillin-resistant Staphylococcus aureus (MRSA) biofilms. The antibiofilm activity of these salts was analyzed in terms of their lipophilicity, capacity to induce transmembrane ion transport, perturbation of the cellular membrane, and mechanism of action in the phospholipid bilayer. The synthesized compounds were not active against MRSA biofilms, as the formation of transmembrane channels had no effect on the integrity of the extracellular polymeric substance matrix and only octyl and adamantyl derivatives possessed the capacity to inhibit biofilm formation. The synthesized derivatives could be used as lead candidates for the development of anti-MRSA agents.
抗生素耐药菌的流行率不断上升，这对人类健康是一个重大挑战。开发新的抗生素药物对于对抗持续感染和降低死亡率至关重要。在这项研究中，我们设计了带有辛基、金刚烷基和胆甾基亲脂性侧链的 2-（1H-苯并咪唑-2-基）乙基-1,1′-联苯-2,2′-二基二（1H-苯并咪唑）盐（lutidine-bis-benzimidazolium 核心），并测试了它们的抗菌活性、抑制浮游细菌和真菌生长的能力，以及抑制或破坏成熟耐甲氧西林金黄色葡萄球菌（MRSA）生物膜形成的能力。这些盐的抗生物膜活性是根据其疏水性、诱导跨膜离子转运的能力、细胞膜扰动以及在磷脂双层中的作用机制来分析的。合成的化合物对 MRSA 生物膜没有活性，因为形成跨膜通道对细胞外多聚物基质的完整性没有影响，只有辛基和金刚烷基衍生物具有抑制生物膜形成的能力。这些合成的衍生物可作为开发抗-MRSA 药物的先导候选物。
