A Novel Use of Allopurinol as A Quorum-Sensing Inhibitor in Pseudomonas aeruginosa.

Ahmed Al Saqr,Wael A H Hegazy,Moataz A Shaldam,El-Sayed Khafagy,Hisham A Abbas,Mohammed F Aldawsari

doi:10.3390/antibiotics10111385

Abstract

Pseudomonas aeruginosa can cause a variety of healthcare-associated infections by its arsenal of virulence factors. Virulence factor production is largely controlled by the cell-to-cell communication system termed quorum sensing (QS). Targeting QS may be a good approach to inhibit the production of virulence factors and attenuate pathogenicity without exerting selective stress on bacterial growth. This will greatly reduce the emergence of resistant mutants. In this work, we investigated the anti-virulence and anti-QS activities of the FDA-approved drug allopurinol against the P. aeruginosa PAO1 strain. Allopurinol at 200 µg/mL (1/10 MIC) significantly decreased the production of the QS-controlled Chromobacterium violaceum CV026 violet pigment violacein and other P. aeruginosa QS-controlled virulence factors phenotypically. Furthermore, allopurinol reduced the infiltration of P. aeruginosa and leucocytes and diminished the congestion in the liver and kidney tissues of infected mice. In silico study showed that allopurinol could compete with the autoinducers on binding to the receptors LasR and RhlR by hydrogen bonding. On the molecular level, qRT-PCR proved that allopurinol showed a significant downregulating effect on all tested QS-encoding genes that regulate virulence factor production. In summary, allopurinol is a promising QS inhibitor that may be useful in the future treatment of P. aeruginosa infection.

Highlights

This study aimed to investigate the possible allopurinol anti-quorum sensing (QS) activity and its effect on P. aeruginosa virulence factors to evaluate the possibility of its clinical application, for instance, topically in the treatment of P. aeruginosa eye infections
There was no significant difference between turbidities of P. aeruginosa overnight cultures grown in the presence or absence of allopurinol at sub-Minimum Inhibitory Concentration (MIC)
Viable counting of overnight cultures of allopurinol-treated and untreated bacteria was performed, and no significant difference was found. These results indicate that allopurinol has no effect on bacterial growth at sub-MIC, and all the tested anti-virulence and anti-QS activities of allopurinol were not a result of its inhibition of growth (Figure 1)

Summary

Introduction

The Gram-negative bacterium, Pseudomonas aeruginosa, is responsible for many types of infections such as those of the eye [1] and burn wounds [2] in addition to acute and chronic respiratory tract infections [3]. To cause such infection, P. aeruginosa employs its arsenal that includes a wide variety of virulence factors such as motility, various proteases, and toxins as reviewed [4,5,6,7]. P. aeruginosa is considered among the most major global health concerns due to the elevated levels of resistance to disinfectants and antibiotics [5,6]

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