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

Abstract

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, <i>α</i>-adrenergic blockers were proposed as an anti-virulence agents through inhibiting the bacterial espionage. The current study aimed to explore the <i>α</i>-blockers' anti-QS activities. Within comprehensive in silico investigation, the binding affinities of seven <i>α</i>-adrenoreceptor blockers were evaluated towards structurally different QS receptors. From the best docked <i>α</i>-blockers into QS receptors, terazosin was nominated to be subjected for further in vivo and in vitro anti-QS and anti-virulence activities against <i>Chromobacterium violaceum</i> and <i>Pseudomonas aeruginosa</i>. Terazosin showed a significant ability to diminish the QS-controlled pigment production in <i>C. violaceum.</i> Moreover, Terazosin decreased the <i>P. aeruginosa</i> biofilm formation and down-regulated its QS-encoding genes. Terazosin protected mice from the <i>P. aeruginosa</i> pathogenesis. In conclusion, <i>α</i>-adrenergic blockers are proposed as promising anti-virulence agents as they hinder QS receptors and inhibit bacterial espionage.