Pseudomonas aeruginosa Citrate Synthase GltA Influences Antibiotic Tolerance and the Type III Secretion System through the Stringent Response.
Pseudomonas aeruginosa Citrate Synthase GltA Influences Antibiotic Tolerance and the Type III Secretion System through the Stringent Response.
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DOI：
10.1128/spectrum.03239-22
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发表时间：
2023-02-14
影响因子：
3.7
通讯作者：
中科院分区：
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碳水化合物代谢在能量生成和为氨基酸合成提供碳骨架中起着至关重要的作用。此外，碳水化合物代谢已被证明影响细菌对抗生素的敏感性和毒性。在本研究中，我们发现柠檬酸合成酶gltA突变可以增加铜绿假单胞菌III型分泌系统（T3SS）基因的表达和抗生素耐受性。严格的反应在gltA突变体中被激活，(p)ppGpp合成酶基因relA的缺失使T3SS基因的抗生素耐受性和表达恢复到野生型水平。我们进一步证明，gltA突变体的严格反应增加了细胞内cAMP水平，从而增加了T3SS主调控基因exsA的表达。总之，我们的研究结果揭示了GltA在P. aeruginosa的代谢、抗生素耐受性和毒力方面的重要作用，以及T3SS在P. aeruginosa的严格响应介导调节中的一种新的调节机制。抗菌素耐药性的上升对人类健康构成严重威胁。迫切需要通过了解细菌对毒力和耐药性决定因素的调控来开发新的抗微生物策略。严格的反应在毒力和抗生素耐受中起着至关重要的作用。铜绿假单胞菌是一种机会致病菌，可引起人类急性和慢性感染。这种细菌产生一系列毒力因子，对多种抗生素具有高度耐药性。在本研究中，我们提供证据表明，柠檬酸合成酶GltA在铜绿假单胞菌的代谢中起关键作用，并影响抗生素耐受性和毒力。我们进一步揭示了严格反应在抗生素耐受性和毒力调节中的作用。这项工作的意义在于阐明了铜绿假单胞菌中控制抗生素耐受性和毒力的新调控途径。
Carbohydrate metabolism plays essential roles in energy generation and providing carbon skeletons for amino acid syntheses. In addition, carbohydrate metabolism has been shown to influence bacterial susceptibility to antibiotics and virulence. In this study, we demonstrate that citrate synthase gltA mutation can increase the expression of the type III secretion system (T3SS) genes and antibiotic tolerance in Pseudomonas aeruginosa. The stringent response is activated in the gltA mutant, and deletion of the (p)ppGpp synthetase gene relA restores the antibiotic tolerance and expression of the T3SS genes to wild-type level. We further demonstrate that the intracellular level of cAMP is increased by the stringent response in the gltA mutant, which increases the expression of the T3SS master regulator gene exsA. Overall, our results reveal an essential role of GltA in metabolism, antibiotic tolerance, and virulence, as well as a novel regulatory mechanism of the stringent response-mediated regulation of the T3SS in P. aeruginosa. IMPORTANCE Rising antimicrobial resistance imposes a severe threat to human health. It is urgent to develop novel antimicrobial strategies by understanding bacterial regulation of virulence and antimicrobial resistance determinants. The stringent response plays an essential role in virulence and antibiotic tolerance. Pseudomonas aeruginosa is an opportunistic pathogen that causes acute and chronic infections in humans. The bacterium produces an arsenal of virulence factors and is highly resistant to a variety of antibiotics. In this study, we provide evidence that citrate synthase GltA plays a critical role in P. aeruginosa metabolism and influences the antibiotic tolerance and virulence. We further reveal a role of the stringent response in the regulation of the antibiotic tolerance and virulence. The significance of this work is in elucidation of novel regulatory pathways that control both antibiotic tolerance and virulence in P. aeruginosa.
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影响因子：
6.4
作者：
Burstein D;Satanower S;Simovitch M;Belnik Y;Zehavi M;Yerushalmi G;Ben-Aroya S;Pupko T;Banin E
通讯作者：
Banin E
氨基酸饥饿对活大肠杆菌中的Rela扩散行为的影响。
影响因子：
3.6
作者：
Li W;Bouveret E;Zhang Y;Liu K;Wang JD;Weisshaar JC
通讯作者：
Weisshaar JC
严格控制核糖体依赖性激活。
影响因子：
64.8
作者：
Brown A;Fernández IS;Gordiyenko Y;Ramakrishnan V
通讯作者：
Ramakrishnan V
影响因子：
6.4
作者：
Gaca AO;Kajfasz JK;Miller JH;Liu K;Wang JD;Abranches J;Lemos JA
通讯作者：
Lemos JA
DOI：
10.1038/nrmicro2199
发表时间：
2009-09
期刊：
Nature reviews. Microbiology
影响因子：
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