A Brominated Furanone Inhibits Pseudomonas aeruginosa Quorum Sensing and Type III Secretion, Attenuating Its Virulence in a Murine Cutaneous Abscess Model
Por:
Munoz-Cazares, Naybi, Castillo-Juarez, Israel, Garcia-Contreras, Rodolfo, Alberto Castro-Torres, Victor, Diaz-Guerrero, Miguel, Rodriguez-Zavala, Jose S., QUEZADA, HECTOR, Gonzalez-Pedrajo, Bertha, Martinez-Vazquez, Mariano
Publicada:
1 ago 2022
Resumen:
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 mu
M) 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 mu M). 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.
Filiaciones:
Munoz-Cazares, Naybi:
Colegio Postgrad, Posgrad Bot, Lab Fitoquim, Texcoco 56230, Mexico
Castillo-Juarez, Israel:
Colegio Postgrad, Posgrad Bot, Lab Fitoquim, Texcoco 56230, Mexico
Garcia-Contreras, Rodolfo:
Univ Nacl Autonoma Mexico, Fac Med, Dept Microbiol & Parasitol, Ciudad Univ, Ciudad De Mexico 04510, Mexico
Alberto Castro-Torres, Victor:
Univ Nacl Autonoma Mexico, Inst Quim, Dept Prod Nat, Ciudad Univ, Ciudad De Mexico 04510, Mexico
Diaz-Guerrero, Miguel:
Univ Nacl Autonoma Mexico, Fac Med, Dept Microbiol & Parasitol, Ciudad Univ, Ciudad De Mexico 04510, Mexico
Univ Nacl Autonoma Mexico, Inst Fisiol Celular, Dept Genet Mol, Ciudad Univ, Ciudad De Mexico 04510, Mexico
Rodriguez-Zavala, Jose S.:
Inst Nacl Cardiol Ignacio Chavez, Dept Bioquim, Ciudad De Mexico 14080, Mexico
QUEZADA, HECTOR:
Hosp Infantil Mexico Dr Federico Gomez, Lab Invest Inmunol & Proteom, Ciudad De Mexico 06720, Mexico
Gonzalez-Pedrajo, Bertha:
Univ Nacl Autonoma Mexico, Inst Fisiol Celular, Dept Genet Mol, Ciudad Univ, Ciudad De Mexico 04510, Mexico
Martinez-Vazquez, Mariano:
Univ Nacl Autonoma Mexico, Inst Quim, Dept Prod Nat, Ciudad Univ, Ciudad De Mexico 04510, Mexico
gold, Green Published, Gold, Green
|