A Brominated Furanone Inhibits Pseudomonas aeruginosa Quorum Sensing and Type III Secretion, Attenuating Its Virulence in a Murine Cutaneous Abscess Model

Abstract

Quorum sensing (QS) and type III secretion systems (T3SSs) are among the most attractive anti-virulence targets for combating multidrug-resistant pathogenic bacteria. Some halogenated furanones reduce QS-associated virulence, but their role in T3SS inhibition remains unclear. This study aimed to assess the inhibition of these two systems on Pseudomonas aeruginosa virulence. The halogenated furanones (Z)-4-bromo-5-(bromomethylene)-2(5H) (C-30) and 5-(dibromomethylene)-2(5H) (named hereafter GBr) were synthesized, and their ability to inhibit the secretion of type III exoenzymes and QS-controlled virulence factors was analyzed in P. aeruginosa PA14 and two clinical isolates. Furthermore, their ability to prevent bacterial establishment was determined in a murine cutaneous abscess model. The GBr furanone reduced pyocyanin production, biofilm formation, and swarming motility in the same manner or more effectively than C-30. Moreover, both furanones inhibited the secretion of ExoS, ExoT, or ExoU effectors in all tested strains. The administration of GBr (25 and 50 µM) to CD1 mice infected with the PA14 strain significantly decreased necrosis formation in the inoculation zone and the systemic spread of bacteria more efficiently than C-30 (50 µM). Molecular docking analysis suggested that the gem position of bromine in GBr increases its affinity for the active site of the QS LasR regulator. Overall, our findings showed that the GBr furanone displayed efficient multi-target properties that may favor the development of more effective anti-virulence therapies.

Evaluation of the antibacterial, antibiofilm, and anti-virulence effects of acetic acid and the related mechanisms on colistin-resistant Pseudomonas aeruginosa

“…AA can impede P. aeruginosa motility and the formation of pyocyanin and elastase. The type III secretion system (T3SS) and quorum sensing (QS) system can regulate P. aeruginosa motility and virulence factor secretion [40]. Therefore, we evaluated the expression of QS-regulated genes, T3SS circuit genes, and the flagellin gene in P. aeruginosa in response to AA.…”

Mitigation of quorum sensing mediated virulence factors of Pseudomonas aeruginosa: the role of Meldrum’s acid activated furan

“…After the wells were allowed to dry, the biofilm bound dye was eluted using 33% glacial acetic acid for 5 min, and the absorbance was measured at 600 nm ( Adonizio et al, 2008 ). Furanone C-30, a known anti-biofilm agent of P. aeruginosa , was used as positive control ( Muñoz-Cázares et al, 1847 ).…”

Impact of Marine Chemical Ecology Research on the Discovery and Development of New Pharmaceuticals

“…Hence, the production of halogenated furanones represents an effective defense strategy used by the seaweed in preventing bacterial infection [ 21 ]. It was also discovered that natural halogenated furanones and their synthetic analogs, e.g., C-30 ( 6 ) and GBr ( 7 ) ( Figure 1 ), inhibit quorum sensing in Pseudomonas aeruginosa , highlighting their potential application as anti-infective agents against pathogenic bacteria [ 25 , 26 ].…”