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Amino acid divergence in the ligand-binding pocket of Vibrio LuxR/HapR proteins determines the efficacy of thiophenesulfonamide inhibitors
Molecular Microbiology ( IF 3.6 ) Pub Date : 2021-09-01 , DOI: 10.1111/mmi.14804 Jane D Newman 1 , Jay Chopra 2 , Priyanka Shah 2 , Eda Shi 2 , Molly E McFadden 2 , Rachel E Horness 2 , Laura C Brown 2 , Julia C van Kessel 1
Molecular Microbiology ( IF 3.6 ) Pub Date : 2021-09-01 , DOI: 10.1111/mmi.14804 Jane D Newman 1 , Jay Chopra 2 , Priyanka Shah 2 , Eda Shi 2 , Molly E McFadden 2 , Rachel E Horness 2 , Laura C Brown 2 , Julia C van Kessel 1
Affiliation
The quorum-sensing signaling systems in Vibrio bacteria converge to control levels of the master transcription factors LuxR/HapR, a family of highly conserved proteins that regulate gene expression for bacterial behaviors. A compound library screen identified 2-thiophenesulfonamide compounds that specifically inhibit Vibrio campbellii LuxR but do not affect cell growth. We synthesized a panel of 50 thiophenesulfonamide compounds to examine the structure–activity relationship effects on Vibrio quorum sensing. The most potent molecule identified, PTSP (3-phenyl-1-(thiophen-2-ylsulfonyl)-1H-pyrazole), inhibits quorum sensing in multiple strains of V. vulnificus, V. parahaemolyticus, and V. campbellii at nanomolar concentrations. However, thiophenesulfonamide inhibition efficacy varies significantly among Vibrio species: PTSP is most inhibitory against V. vulnificus SmcR, but V. cholerae HapR is completely resistant to all thiophenesulfonamides tested. Reverse genetics experiments show that PTSP efficacy is dictated by amino acid sequence in the putative ligand-binding pocket: F75Y and C170F SmcR substitutions are each sufficient to eliminate PTSP inhibition. Further, in silico modeling distinguished the most potent thiophenesulfonamides from less-effective derivatives. Our results revealed the previously unknown differences in LuxR/HapR proteins that control quorum sensing in Vibrio species and underscore the potential for developing thiophenesulfonamides as specific quorum sensing-directed treatments for Vibrio infections.
中文翻译:
弧菌 LuxR/HapR 蛋白配体结合口袋中的氨基酸差异决定了噻吩磺酰胺抑制剂的功效
弧菌细菌中的群体感应信号系统汇聚以控制主转录因子 LuxR/HapR 的水平,LuxR/HapR 是一个高度保守的蛋白质家族,可调节细菌行为的基因表达。化合物库筛选确定了 2-噻吩磺酰胺化合物,该化合物可特异性抑制Vibrio campbellii LuxR 但不影响细胞生长。我们合成了一组 50 种噻吩磺酰胺化合物,以检查构效关系对弧菌群体感应的影响。鉴定出的最有效分子,PTSP (3- p henyl -1-( t hiophen-2-yl s ulfonyl)-1 H - pyrazole),在纳摩尔浓度下抑制创伤弧菌、副溶血弧菌和坎贝氏弧菌的多种菌株的群体感应。然而,噻吩磺酰胺抑制效果在不同弧菌种类之间有显着差异:PTSP 对创伤弧菌 SmcR 的抑制作用最强,但对霍乱弧菌的抑制作用最大HapR 对所有测试的噻吩磺酰胺完全耐受。反向遗传学实验表明,PTSP 功效由假定的配体结合口袋中的氨基酸序列决定:F75Y 和 C170F SmcR 替换均足以消除 PTSP 抑制。此外,计算机模拟将最有效的噻吩磺酰胺与效果较差的衍生物区分开来。我们的研究结果揭示了控制弧菌种群感应的 LuxR/HapR 蛋白以前未知的差异,并强调了开发噻吩磺酰胺作为弧菌感染的特定群体感应导向治疗的潜力。
更新日期:2021-10-25
中文翻译:
弧菌 LuxR/HapR 蛋白配体结合口袋中的氨基酸差异决定了噻吩磺酰胺抑制剂的功效
弧菌细菌中的群体感应信号系统汇聚以控制主转录因子 LuxR/HapR 的水平,LuxR/HapR 是一个高度保守的蛋白质家族,可调节细菌行为的基因表达。化合物库筛选确定了 2-噻吩磺酰胺化合物,该化合物可特异性抑制Vibrio campbellii LuxR 但不影响细胞生长。我们合成了一组 50 种噻吩磺酰胺化合物,以检查构效关系对弧菌群体感应的影响。鉴定出的最有效分子,PTSP (3- p henyl -1-( t hiophen-2-yl s ulfonyl)-1 H - pyrazole),在纳摩尔浓度下抑制创伤弧菌、副溶血弧菌和坎贝氏弧菌的多种菌株的群体感应。然而,噻吩磺酰胺抑制效果在不同弧菌种类之间有显着差异:PTSP 对创伤弧菌 SmcR 的抑制作用最强,但对霍乱弧菌的抑制作用最大HapR 对所有测试的噻吩磺酰胺完全耐受。反向遗传学实验表明,PTSP 功效由假定的配体结合口袋中的氨基酸序列决定:F75Y 和 C170F SmcR 替换均足以消除 PTSP 抑制。此外,计算机模拟将最有效的噻吩磺酰胺与效果较差的衍生物区分开来。我们的研究结果揭示了控制弧菌种群感应的 LuxR/HapR 蛋白以前未知的差异,并强调了开发噻吩磺酰胺作为弧菌感染的特定群体感应导向治疗的潜力。