Repurposing α-Adrenoreceptor Blockers as Promising Anti-Virulence Agents in Gram-Negative Bacteria

Antimicrobial resistance is among the world's most urgent public health problems. Diminishing of the virulence of bacteria is a promising approach to decrease the development of bacterial resistance. Quorum sensing (QS) systems orchestrate the bacterial virulence in inducer-receptors manner. Bacteria can spy on the cells of the host by sensing adrenergic hormones and other neurotransmitters, and in turn, these neurotransmitters can induce bacterial pathogenesis. In this direction, alpha-adrenergic blockers were proposed as an anti-virulence agents through inhibiting the bacterial espionage. The current study aimed to explore the alpha-blockers' anti-QS activities. Within comprehensive in silico investigation, the binding affinities of seven alpha-adrenoreceptor blockers were evaluated towards structurally different QS receptors. From the best docked alpha-blockers into QS receptors, terazosin was nominated to be subjected for further in vivo and in vitro anti-QS and anti-virulence activities against Chromobacterium violaceum and Pseudomonas aeruginosa. Terazosin showed a significant ability to diminish the QS-controlled pigment production in C. violaceum. Moreover, Terazosin decreased the P. aeruginosa biofilm formation and down-regulated its QS-encoding genes. Terazosin protected mice from the P. aeruginosa pathogenesis. In conclusion, alpha-adrenergic blockers are proposed as promising anti-virulence agents as they hinder QS receptors and inhibit bacterial espionage.

Automated summary

Antimicrobial resistance is a pressing global public health issue. This study investigates the potential of blocking adrenergic receptors as a strategy to reduce bacterial virulence and inhibit the development of resistance. The researchers found that terazosin, an alpha-adrenergic blocker, showed promising anti-quorum sensing (QS) and anti-virulence activities against two bacteria strains. It effectively reduced pigment production in one strain and inhibited biofilm formation and down-regulated QS genes in another strain.