Singapore Centre for Environmental Life Sciences Engineering, Nanyang Technological University, Singapore, Singapore.
Department of Chemistry, Technical University of Denmark, Lyngby, Denmark.
Front Cell Infect Microbiol. 2019 Jan 7;8:443. doi: 10.3389/fcimb.2018.00443. eCollection 2018.
is known as an opportunistic pathogen that often causes persistent infections associated with high level of antibiotic-resistance and biofilms formation. Chemical interference with bacterial cell-to-cell communication, termed quorum sensing (QS), has been recognized as an attractive approach to control infections and address the drug resistance problems currently observed worldwide. Instead of imposing direct selective pressure on bacterial growth, the right bioactive compounds can preferentially block QS-based communication and attenuate cascades of bacterial gene expression and production of virulence factors, thus leading to reduced pathogenicity. Herein, we report on the potential of itaconimides as quorum sensing inhibitors (QSI) of . An initial hit was discovered in a screening program of an in-house compound collection, and subsequent structure-activity relationship (SAR) studies provided analogs that could reduce expression of central QS-regulated virulence factors (elastase, rhamnolipid, and pyocyanin), and also successfully lead to the eradication of biofilms in combination with tobramycin. Further studies on the cytotoxicity of compounds using murine macrophages indicated no toxicity at common working concentrations, thereby pointing to the potential of these small molecules as promising entities for antimicrobial drug development.
它被认为是一种机会性病原体，常引起持续性感染，且具有高水平抗生素耐药性和生物膜形成。细菌细胞间通讯的化学干扰，称为群体感应（QS），已被认为是一种有吸引力的控制感染和解决目前全球范围内观察到的耐药问题的方法。与直接对细菌生长施加选择性压力不同，合适的生物活性化合物可以优先阻断基于 QS 的通讯，并减弱细菌基因表达和毒力因子产生的级联反应，从而降低致病性。在此，我们报告了衣康酸亚胺作为. 的群体感应抑制剂（QSI）的潜力。在内部化合物库的筛选计划中发现了一个初始命中物，随后的构效关系（SAR）研究提供了能够降低中央 QS 调节毒力因子（弹性蛋白酶、鼠李糖脂和绿脓菌素）表达的类似物，并且还成功地与妥布霉素联合消除了生物膜。使用小鼠巨噬细胞对化合物的细胞毒性进一步研究表明，在常见工作浓度下没有毒性，这表明这些小分子作为有前途的抗菌药物开发实体具有潜力。
