Effect of Autoinducer-2 Quorum Sensing Inhibitor on Interspecies Quorum Sensing

Abstract

Bacterial drug resistance caused by overuse and misuse of antibiotics is common, especially in clinical multispecies infections. It is of great significance to discover novel agents to treat clinical bacterial infections. Studies have demonstrated that autoinducer-2 (AI-2), a signal molecule in quorum sensing (QS), plays an important role in communication among multiple bacterial species and bacterial drug-resistance. Previously, 14 AI-2 inhibited compounds were selected through virtual screening by using the AI-2 receptor protein LuxP as a target. Here, we used <i>Vibrio harveyi</i> BB170 as a reporter strain for the preliminary screening of 14 inhibitors and compound Str7410 had higher AI-2 QS inhibition activity (IC₅₀ = 0.3724 ± 0.1091 μM). Then, co-culture of <i>Pseudomonas aeruginosa</i> PAO1 with <i>Staphylococcus aureus</i> ATCC 25923 was used to evaluate the inhibitory effects of Str7410 on multispecies infection <i>in vitro</i> and <i>in vivo</i>. <i>In vitro</i>, Str7410 significantly inhibited the formation of mixed bacterial biofilms. Meanwhile, the combination of Str7410 with meropenem trihydrate (MEPM) significantly improved the susceptibility of mixed-species-biofilm cells to the antibiotic. <i>In vivo</i>, Str7410 significantly increased the survival rate of wild-type <i>Caenorhabditis elegans</i> N2 co-infected by <i>P. aeruginosa</i> PAO1 and <i>S. aureus</i> ATCC 25923. Real-time quantitative PCR analysis showed that Str7410 reduced virulence factor (pyocyanin and elastase) production and swarming motility of <i>P. aeruginosa</i> PAO1 by downregulating the expression of QS-related genes in strain PAO1 in co-culture with <i>S. aureus</i> ATCC 25923. Compound Str7410 is a candidate agent for treating drug-resistant multispecies infections. The work described here provides a strategy for discovering novel antibacterial drugs.