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Cell envelope stress responses and the mechanism of antibiotic tolerance in Gram-negative pathogens

革兰氏阴性病原体的细胞包膜应激反应和抗生素耐受机制

基本信息

批准号：
10543069
负责人：
Tobias Doerr
金额：
$ 39.16万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-10 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10543069
关键词：
Acinetobacter baumannii Adjuvant Aftercare Anti-Bacterial Agents Antibiotic Resistance Antibiotic Therapy Antibiotics Bacteria Biochemical Biological Models Cell Shape Cell Wall Cell membrane Cells ChIP-seq Cholera Clinical Clinical Treatment Complex Data Data Set Development Down-Regulation Drug Targeting Enterobacter cloacae Excision Exhibits Exposure to Genes Genetic Goals Gram-Negative Bacteria Haemophilus influenzae Homeostasis Homologous Gene In Vitro Individual Infection Iron Knowledge Learning Lipids Maintenance Measures Mediating Membrane Metabolic Metals Microbe Modeling Modern Medicine Normal Cell Pathway interactions Penicillins Phospholipids Population Predisposition Pseudomonas aeruginosa Recovery Regulon Resistance Resolution Role Shapes Signal Induction Stress Superoxide Dismutase System Testing Translating Treatment Failure Up-Regulation Vibrio cholerae Withdrawal antibiotic design antibiotic tolerance antimicrobial bactericide beta-Lactams biological adaptation to stress candidate identification cell envelope cell motility clinical practice design drug action experimental study in vivo insight member membrane synthesis model organism novel pathogen protein-histidine kinase rapid growth recurrent infection repaired response transcriptome sequencing

项目摘要

Project Summary Bacteria often resist killing by normally bactericidal antibiotics, resulting in clinical treatment failure and the development of antibiotic resistance. The ability to survive damage elicited by exposure to antibiotics is termed tolerance. Tolerance is likely responsible for the recurrence of infections after discontinuation of antimicrobial therapy, and provides a reservoir of a bacterial population that can develop full scale resistance. An extreme case of tolerance is the formation of persister cells, which do not experience antibiotic-induced damage due to dormancy. However, we and others have found that many Gram-negative pathogens (Vibrio cholerae, Pseudomonas aeruginosa, Enterobacter cloacae, Haemophilus influenzae and Acinetobacter baumannii) are fully susceptible to damage induced by cell wall acting antibiotics (beta lactams), but yet survive at very high levels. Survival is enabled through the formation of viable spheres that are devoid of detectable cell wall material and that recover to normal shape upon withdrawal of the antibiotic. In our model organism, the cholera pathogen V. cholerae, tolerance is promoted by cell envelope stress responses, especially the two-component system WigKR. WigKR is induced by cell wall acting antibiotics and mounts a complex response that ultimately enables recovery from the spherical state. This response includes upregulation of cell wall synthesis functions, outer membrane synthesis, phospholipid synthesis and downregulation of motility and iron acquisition genes. How this response promotes tolerance is poorly understood, and so are the mechanisms of tolerance in other Gram-negative bacteria. Here, we aim to interrogate V. cholerae's cell envelope stress responses and their relationship with beta lactam tolerance and post-antibiotic recovery. Using genetic and biochemical approaches, we will find the elusive induction signal sensed by the histidine kinase WigK. Leveraging extensive datasets comprehensively describing the WigKR regulon, we will measure each individual regulon member's contribution to beta lactam tolerance. Lastly, we will apply what we have learned in the V. cholerae model to other Gram-negative pathogens exhibiting high beta lactam tolerance, specifically E. cloacae and P. aeruginosa. Our experiments will yield novel insight into the mechanisms of antibiotic tolerance and result in the identification of candidate drug targets for anti-tolerance adjuvants of beta lactams.

项目概要细菌常常无法抵抗通常具有杀菌作用的抗生素的杀灭，从而导致临床治疗失败和抗生素耐药性的发展。抵抗因接触抗生素而引起的损害的能力被称为宽容。耐药性可能是停用抗菌药物后感染复发的原因疗法，并提供可以产生全面耐药性的细菌群体的储存库。一个极端耐受的情况是持续细胞的形成，这些细胞不会因抗生素引起的损伤休眠。然而，我们和其他人发现许多革兰氏阴性病原体（霍乱弧菌、铜绿假单胞菌、阴沟肠杆菌、流感嗜血杆菌和鲍曼不动杆菌）完全容易受到细胞壁作用抗生素（β内酰胺）引起的损伤，但仍能在非常高的条件下存活水平。通过形成没有可检测到的细胞壁的活球体来实现生存材料，并在停用抗生素后恢复正常形状。在我们的模型生物中，霍乱对于病原体霍乱弧菌，细胞包膜应激反应可促进耐受性，尤其是双组分系统假发KR。 WigKR 由细胞壁作用的抗生素诱导，并产生复杂的反应，最终使得能够从球形状态恢复。这种反应包括细胞壁合成功能的上调，外膜合成、磷脂合成以及运动性和铁获取基因的下调。人们对这种反应如何促进耐受性知之甚少，其他方面的耐受机制也是如此。革兰氏阴性细菌。在这里，我们的目标是探究霍乱弧菌的细胞包膜应激反应及其与β内酰胺耐受性和抗生素后恢复的关系。利用遗传和生化通过这种方法，我们会发现组氨酸激酶 WigK 感应到的难以捉摸的诱导信号。杠杆作用全面描述 WigKR 调节子的广泛数据集，我们将测量每个单独的调节子成员对β内酰胺耐受性的贡献。最后，我们将应用我们在霍乱弧菌中学到的知识其他表现出高β内酰胺耐受性的革兰氏阴性病原体的模型，特别是阴沟肠杆菌和假单胞菌。铜绿假单胞菌。我们的实验将对抗生素耐受机制产生新的见解，并导致 β内酰胺抗耐受佐剂候选药物靶标的鉴定。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Bacterial metabolism and susceptibility to cell wall-active antibiotics.

细菌代谢和对细胞壁活性抗生素的敏感性。

DOI：
10.1016/bs.ampbs.2023.04.002
发表时间：
2023
期刊：
Advances in microbial physiology
影响因子：
0
作者：
Keller,MeganRenee;Dörr,Tobias
通讯作者：
Dörr,Tobias

Understanding tolerance to cell wall-active antibiotics.

DOI：
10.1111/nyas.14541
发表时间：
2021-07
期刊：
Annals of the New York Academy of Sciences
影响因子：
5.2
作者：
Dörr T
通讯作者：
Dörr T

Peptidoglycan Recycling Promotes Outer Membrane Integrity and Carbapenem Tolerance in Acinetobacter baumannii.

DOI：
10.1128/mbio.01001-22
发表时间：
2022-06-28
期刊：
mBio
影响因子：
6.4
作者：
通讯作者：

High-level carbapenem tolerance requires antibiotic-induced outer membrane modifications.

DOI：
10.1371/journal.ppat.1010307
发表时间：
2022-03
期刊：
PLoS pathogens
影响因子：
6.7
作者：
Murtha AN;Kazi MI;Schargel RD;Cross T;Fihn C;Cattoir V;Carlson EE;Boll JM;Dörr T
通讯作者：
Dörr T

Analysis of AcrB in Klebsiella pneumoniae reveals natural variants promoting enhanced multidrug resistance.