Pseudomonas aeruginosa is a significant human pathogen, it possesses almost all of the known antimicrobial resistance mechanisms. Quorum sensing (QS) is an intercellular communication system that orchestrates bacterial virulence and its targeting is an effective approach to diminish its pathogenesis. Repurposing of drugs is an advantageous strategy, in this study we aimed to repurpose the anti-diabetic drugs sitagliptin, metformin and vildagliptin as anti-QS in P. aeruginosa. The effects of sub-inhibitory concentrations of the tested drugs on the expression of QS-encoding genes and QS-regulated virulence factors were assessed. The protective activity of tested drugs on P. aeruginosa pathogenesis was evaluated in vivo on mice. In silico analysis was performed to evaluate the interference capabilities of the tested drugs on QS-receptors. Although the three drugs reduced the expression of QS-encoding genes, only sitagliptin inhibited the P. aeruginosa virulence in vitro and protected mice from it. In contrast, metformin showed significant in vitro anti-QS activities but failed to protect mice from P. aeruginosa. Vildagliptin did not show any in vitro or in vivo efficacy. Sitagliptin is a promising anti-QS agent because of its chemical nature that hindered QS-receptors. Moreover, it gives an insight to consider their similar chemical structures as anti-QS agents or even design new chemically similar anti-QS pharmacophores.

Serratia marcescens is an opportunistic nosocomial pathogen and causes wound and burn infections. It shows high resistance to antibiotics and its pathogenicity is mediated by an arsenal of virulence factors. Another therapeutic option to such infections is targeting quorum sensing (QS), which controls the expression of different S. marcescens virulence factors. Prevention of QS can deprive S. marcescens from its bacterial virulence without applying stress on the bacterial growth and facilitates the eradication of the bacteria by immunity. The objective of the current study is to explore the antimicrobial and antivirulence activities of xylitol against S. marcescens. Xylitol could inhibit the growth of S. marcescens. Sub-inhibitory concentrations of xylitol could inhibit biofilm formation, reduce prodigiosin production, and completely block protease activity. Moreover, xylitol decreased swimming motility, swarming motility and increased the sensitivity to hydrogen peroxide. The expression of rsmA, pigP, flhC, flhD fimA, fimC, shlA bsmB, and rssB genes that regulate virulence factor production was significantly downregulated by xylitol. In silico study showed that xylitol could bind with the SmaR receptor by hydrophobic interaction and hydrogen bonding, and interfere with the binding of the natural ligand with SmaR receptor. An in vivo mice survival test confirmed the ability of xylitol to protect mice against the virulence of S. marcescens. In conclusion, xylitol is a growth and virulence inhibitor in S. marcescens and can be employed for the treatment of S. marcescens wound and burn infections.

Bacterial resistance to antibiotics is an increasing public health threat as it has the potential to affect people at any stage of life, as well as veterinary. Various approaches have been proposed to counteract the bacterial resistance development. Tackling bacterial virulence is one of the most promising approaches that confer several merits. The bacterial virulence is mainly regulated by a communication system known as quorum sensing (QS) system. Meanwhile, bacteria can sense the adrenergic hormones and eavesdrops on the host cells to establish their infection, adrenergic hormones were shown to enhance the bacterial virulence. In this study, β-adrenoreceptor blockers were proposed not only to stop bacterial espionage on our cells but also as inhibitors to the bacterial QS systems. In this context, a detailed in silico study has been conducted to evaluate the affinities of twenty-two β-blockers to compete on different structural QS receptors. Among the best docked and thermodynamically stable β-blockers; atenolol, esmolol, and metoprolol were subjected to further in vitro and in vivo investigation to evaluate their anti-QS activities against Chromobacterium violaceum, Pseudomonas aeruginosa and Salmonella typhimurium. The three tested β-blockers decreased the production of QS-controlled C. violaceum, and the formation of biofilm by P. aeruginosa and S. typhimurium. Additionally, the tested β-blockers down-regulated the P. aeruginosa QS-encoding genes and S. typhimurium sensor kinase encoding genes. Furthermore, metoprolol protected mice against P. aeruginosa and S. typhimurium. Conclusively, these investigated β-blockers are promising anti-virulence agents antagonizing adrenergic hormones induced virulence, preventing bacterial espionage, and blocking bacterial QS systems.