Abstract：
Quorum sensing (QS) has a central role in biofilm lifestyle and antimicrobial resistance, and disrupting these signaling pathways is a promising strategy to control bacterial pathogenicity and virulence. In this study, the efficacy of three structurally related benzaldehydes (4-hydroxybenzaldehyde, 4-hydroxy-3-methoxybenzaldehyde (vanillin) and 4-hydroxy-3,5-dimethoxybenzaldehyde (syringaldehyde)) in disrupting the las and pqs systems of Pseudomonas aeruginosa was investigated using bioreporter strains and computational simulations. Additionally, these benzaldehydes were combined with tobramycin and ciprofloxacin antibiotics to evaluate their ability to increase antibiotic efficacy in preventing and eradicating P. aeruginosa biofilms. To this end, the total biomass, metabolic activity and culturability of the biofilm cells were determined. In vitro assays results indicated that the aromatic aldehydes have potential to inhibit the las and pqs systems by > 80 %. Molecular docking studies supported these findings, revealing the aldehydes binding in the same pocket as the natural ligands or receptor proteins (LasR, PQSA, PQSE, PQSR). Benzaldehydes were shown to act as virulence factor attenuators, with vanillin achieving a 48 % reduction in pyocyanin production. The benzaldehyde-tobramycin combination led not only to a 60 % reduction in biomass production but also to a 90 % reduction in the metabolic activity of established biofilms. A similar result was observed when benzaldehydes were combined with ciprofloxacin. 4-Hydroxybenzaldehyde demonstrated relevant action in increasing biofilm susceptibility to ciprofloxacin, resulting in a 65 % reduction in biomass. This study discloses, for the first time, that the benzaldehydes studied are potent QS inhibitors and also enhancers of antibiotics antibiofilm activity against P. aeruginosa.
摘要：
群体感应（QS）在生物膜生活方式和抗菌素耐药性中起着核心作用，破坏这些信号通路是控制细菌致病性和毒力的有前途的策略。在这项研究中,三种结构相关的苯甲醛(4-羟基苯甲醛，使用生物报告菌株和计算模拟研究了4-羟基-3-甲氧基苯甲醛（香草醛）和4-羟基-3,5-二甲氧基苯甲醛（丁香醛））在破坏铜绿假单胞菌的las和pqs系统中的作用。此外,将这些苯甲醛与妥布霉素和环丙沙星抗生素联合使用,以评估它们在预防和根除铜绿假单胞菌生物膜中提高抗生素疗效的能力.为此,总生物量，确定了生物膜细胞的代谢活性和可培养性。体外测定结果表明芳族醛具有>80%的抑制las和pqs系统的潜力。分子对接研究支持了这些发现，揭示醛与天然配体或受体蛋白（LasR，PQSA,PQSE,PQSR）。苯甲醛被证明是毒力因子衰减剂，香草醛实现了48％的减少，在生产的绿脓苷。苯甲醛-妥布霉素组合不仅导致生物质产量减少60%,而且导致已建立的生物膜的代谢活性减少90%。当苯甲醛与环丙沙星组合时,观察到类似的结果。4-羟基苯甲醛在增加生物膜对环丙沙星的敏感性方面表现出相关作用，导致生物量减少65%。这项研究揭示了，第一次,研究的苯甲醛是有效的QS抑制剂，也是抗生素抗铜绿假单胞菌活性的增强剂。
