Muñoz-Cázares Naybi, Castillo-Juárez Israel, García-Contreras Rodolfo, Castro-Torres Víctor Alberto, Díaz-Guerrero Miguel, Rodríguez-Zavala José S, Quezada Héctor, González-Pedrajo Bertha, Martínez-Vázquez Mariano
Laboratorio de Fitoquímica, Posgrado en Botánica, Colegio de Postgraduados, Texcoco 56230, Mexico.
Departamento de Microbiología y Parasitología, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad Universitaria, Ciudad de México 04510, Mexico.
Biomedicines. 2022 Jul 31;10(8):1847. doi: 10.3390/biomedicines10081847.
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 virulence. The halogenated furanones ()-4-bromo-5-(bromomethylene)-2(5) (C-30) and 5-(dibromomethylene)-2(5) (named hereafter GBr) were synthesized, and their ability to inhibit the secretion of type III exoenzymes and QS-controlled virulence factors was analyzed in 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.
群体感应（QS）和III型分泌系统（T3SSs）是对抗多重耐药病原菌最具吸引力的抗毒力靶点。一些卤代呋喃酮可降低与群体感应相关的毒力，但其在抑制T3SS方面的作用仍不清楚。本研究旨在评估这两种系统对毒力的抑制作用。合成了卤代呋喃酮（）-4-溴-5-（溴亚甲基）-2（5）（C-30）和5-（二溴亚甲基）-2（5）（以下简称GBr），并在PA14和两个临床分离株中分析了它们抑制III型外酶分泌和群体感应控制的毒力因子的能力。此外，在小鼠皮肤脓肿模型中确定了它们预防细菌定植的能力。GBr呋喃酮以与C-30相同或更有效的方式降低了绿脓菌素的产生、生物膜形成和群游运动性。此外，两种呋喃酮在所有测试菌株中均抑制了ExoS、ExoT或ExoU效应器的分泌。给感染PA14菌株的CD1小鼠施用GBr（25和50μM）比C-30（50μM）更有效地显著减少了接种部位的坏死形成和细菌的全身扩散。分子对接分析表明，GBr中溴的偕位增加了其对群体感应LasR调节因子活性位点的亲和力。总体而言，我们的研究结果表明，GBr呋喃酮具有有效的多靶点特性，可能有利于开发更有效的抗毒力疗法。
