Repurposing metformin as a quorum sensing inhibitor in <i>Pseudomonas aeruginosa</i>

Abstract

BackgroundQuorum sensing is a mechanism of intercellular communication that controls the production of virulence factors in Pseudomonas aeruginosa. Inhibition of quorum sensing can disarm the virulence factors without exerting stress on bacterial growth that leads to emergence of antibiotic resistance.ObjectivesFinding a new quorum sensing inhibitor and determining its inhibitory activities against virulence factors of Pseudomonas aeruginosa PAO1 strain.MethodsQuorum sensing was evaluated by estimation of violacein production by Chromobacterium violaceum CV026. Molecular docking was used to investigate the possible binding of metformin to LasR and rhlR receptors. The inhibition of pyocyanin, hemolysin, protease, elastase in addition to swimming and twitching motilities, biofilm formation and resistance to oxidative stress by metformin was also assessed.ResultsMetformin significantly reduced the production of violacein pigment. Significant inhibition of pyocyanin, hemolysin, protease and elastase was achieved. Metformin markedly decreased biofilm formation, swimming and twitching motilities and increased the sensitivity to oxidative stress. In the molecular docking study, metformin could bind to LasR by hydrogen bonding and electrostatic interaction and to rhlR by hydrogen bonding only.ConclusionMetformin can act as a quorum sensing inhibitor and virulence inhibiting agent that may be useful in the treatment of Pseudomonas aeruginosa infection.

Perturbation of Quorum Sensing in &lt;i&gt;Pseudomonas aeruginosa&lt;/i&gt; by Febuxostat

“…As a result, many reports tested the possibility of finding QS inhibitors among FDA approved drugs to make their use possible on clinical background. This hypothesis was found to be true in our previous studies [32] [33].…”

Drugs Repurposing for Multi-Drug Resistant Bacterial Infections

“…Different agents are promising both in vitro and in vivo candidates to be repositioned as antimicrobial agents to treat infections caused by MDR Gram-negative bacilli. A variety of drugs with different mechanisms of action and targets have been selected including: DNA, RNA and proteins inhibitors [16][17][18][19][20], QS regulators [15,17,[21][22][23][24][25], biofilm formation inhibitors and disruptors [26,27], drugs that interact with cell membrane [28][29][30], drugs that interact with iron metabolism [31][32][33][34][35], and host immune system modulators [36][37][38][39]. These drugs and their mechanisms of action against critical-priority pathogens (A. baumannii, P. aeruginosa and Enterobacterales) are summarized in Figure 1 and Table 1.…”

Targeting virulence factors as an antimicrobial approach: Pigment inhibitors

“…Secnidazole ( 73 ), a known nitroimidazole drug, has been used for the treatment of many infections caused by anaerobic pathogens and has shown a powerful inhibitory effect on P. aeruginosa virulence factors in recent studies . The antidiabetic agent metformin ( 74 ) and the Chinese herb phillyrin ( 75 ) were also identified to significantly reduce the production of the pigments violacein and pyocyanin in recent studies …”

“…155 The antidiabetic agent metformin (74) and the Chinese herb phillyrin (75) were also identified to significantly reduce the production of the pigments violacein and pyocyanin in recent studies. 156,157 3.8 | Other strategies to discover pyocyanin inhibitors Signaling molecule analogs exhibit excellent anti-pyocyanin activity and attenuate QS virulence. However, no autoinducer-type drugs have been used in clinical P. aeruginosa treatment thus far.…”