The Short-chain Fatty Acid Propionic Acid Activates the Rcs Stress Response System Partially through Inhibition of d-Alanine Racemase.
The Short-chain Fatty Acid Propionic Acid Activates the Rcs Stress Response System Partially through Inhibition of d-Alanine Racemase.
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肠杆菌RCS应激反应系统通过一个复杂的双组分磷酸传递系统对包膜应激做出反应，调节多种环境反应基因，如壳多糖和鞭毛生物合成基因。然而，除了大肠杆菌，激活RCS的压力还没有被很好地理解。在这项研究中，我们使用依赖于RCS系统的发光转录报告来筛选包含240多种抗菌化合物的文库，以寻找那些激活粘质沙雷氏菌RCS系统的化合物，粘质沙雷氏菌是耶尔西尼亚科细菌。使用等基因的RCSB突变体来建立特异性，鉴定出了新的和预期的激活剂，包括短链脂肪酸丙酸，它在人类肠道中发现的水平是毫米级的。丙酸并不能降低细菌细胞内的pH值，这是其抗菌机制的假设。相反，数据表明，丙酸激活RCS的部分原因是丙氨酸消旋酶失活。这种酶负责d-丙氨酸的生物合成，d-丙氨酸是一种产生细菌细胞壁所需的氨基酸。与在粘质链霉菌中观察到的一致，在大肠杆菌中，丙氨酸外消旋酶突变体以d-丙氨酸依赖和RCSB依赖的方式显示RCS报告基因的表达增加。这些结果表明，宿主肠道短链脂肪酸可以通过激活RCS应激反应系统来影响细菌的行为。重要性RCS细菌应激反应系统通过全球改变基因表达来响应包膜压力，从而深刻影响宿主与病原体的相互作用、毒力和抗生素耐受性。在这项研究中，一个发光的RCS报告质粒被用来筛选RCS激活剂的化合物文库。其中最强的诱导剂是短链脂肪酸丙酸，它在人体肠道中含量很高。这项研究表明，肠道短链脂肪酸可以通过诱导RCS系统影响细菌毒力和抗生素耐受性。
The Enterobacterial Rcs stress response system reacts to envelope stresses through a complex two-component phosphorelay system to regulate a variety of environmental response genes, such as capsular polysaccharide and flagella biosynthesis genes. However, beyond Escherichia coli, the stresses that activate Rcs are not well-understood. In this study, we used a Rcs system-dependent luminescent transcriptional reporter to screen a library of over 240 antimicrobial compounds for those that activated the Rcs system in Serratia marcescens, a Yersiniaceae family bacterium. Using an isogenic rcsB mutant to establish specificity, both new and expected activators were identified, including the short-chain fatty acid propionic acid, which is found at millimolar levels in the human gut. Propionic acid did not reduce the bacterial intracellular pH, as was hypothesized for its antibacterial mechanism. Instead, data suggest that the Rcs-activation by propionic acid is due, in part, to an inactivation of alanine racemase. This enzyme is responsible for the biosynthesis of d-alanine, which is an amino-acid that is required for the generation of bacterial cell walls. Consistent with what was observed in S. marcescens, in E. coli, alanine racemase mutants demonstrated elevated expression of the Rcs-reporter in a d-alanine-dependent and RcsB-dependent manner. These results suggest that host gut short-chain fatty acids can influence bacterial behavior via the activation of the Rcs stress response system. IMPORTANCE The Rcs bacterial stress response system responds to envelope stresses by globally altering gene expression to profoundly impact host-pathogen interactions, virulence, and antibiotic tolerance. In this study, a luminescent Rcs-reporter plasmid was used to screen a library of compounds for activators of Rcs. Among the strongest inducers was the short-chain fatty acid propionic acid, which is found at high concentrations in the human gut. This study suggests that gut short-chain fatty acids can affect both bacterial virulence and antibiotic tolerance via the induction of the Rcs system.
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影响因子：
5.7
作者：
Arce-Rodriguez, Alejandro;Volke, Daniel C.;Nikel, Pablo I.
通讯作者：
Nikel, Pablo I.
DOI：
10.3390/antibiotics10091033
发表时间：
2021-08-25
期刊：
Antibiotics (Basel, Switzerland)
影响因子：
--
作者：
Harshaw NS;Stella NA;Lehner KM;Romanowski EG;Kowalski RP;Shanks RMQ
通讯作者：
Shanks RMQ
影响因子：
30.3
作者：
Dalebroux, Zachary D.;Edrozo, Mauna B.;Miller, Samuel I.
通讯作者：
Miller, Samuel I.
影响因子：
2.1
作者：
Huang, Ya-Hui;Ferrieres, Lionel;Clarke, David J.
通讯作者：
Clarke, David J.
DOI：
10.1073/pnas.120163297
发表时间：
2000-06-06
影响因子：
11.1
作者：
Datsenko, KA;Wanner, BL
通讯作者：
Wanner, BL