Cyclic AMP is a global virulence regulator governing inter and intrabacterial signalling in Acinetobacter baumannii.

IF 5.5 1区 医学 Q1 MICROBIOLOGY
PLoS Pathogens Pub Date : 2024-09-06 eCollection Date: 2024-09-01 DOI:10.1371/journal.ppat.1012529
Lyuboslava G Harkova, Rubén de Dios, Alejandro Rubio-Valle, Antonio J Pérez-Pulido, Ronan R McCarthy
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引用次数: 0

Abstract

Acinetobacter baumannii is an opportunistic nosocomial pathogen with high morbidity and mortality rates. Current treatment options for this pathogen are limited due to its increasing resistance to last-resort antibiotics. Despite A. baumannii's leading position in the World Health Organisations priority pathogens list, little is known about its virulence regulation. Through a high-throughput screening approach to identify novel biofilm regulators, we identified a previously uncharacterised predicted adenylate cyclase (AC), CavA, as a central regulator of this phenotype. cAMP is a crucial mediator of various aspects of bacterial physiology in other species but information about its role in A. baumannii is limited. We confirm that CavA AC is functional and synthesizes cAMP in A. baumannii. Using dRNA-seq, we verify that CavA is a negative biofilm formation regulator affecting Csu pili and exopolysaccharide production. We demonstrate for the first time that in A. baumannii, cAMP is atop of a hierarchical signalling cascade controlling inter- and intrabacterial signalling by modulating quorum sensing and cyclic di-GMP systems, ultimately governing virulence in vivo and adaptive antibiotic resistance. In contrast to the well-established paradigm in other bacteria where cAMP and cyclic di-GMP levels are inversely regulated, we uncover that the levels of these second messengers are directly proportional in A. baumannii. Overall, this study uncovers the central role of CavA and cAMP in the pathogenic success of A. baumannii and highlights this signalling cascade as a high potential target for novel therapeutic development.

环磷酸腺苷是一种全球性毒力调节因子,可调节鲍曼不动杆菌细菌间和细菌内的信号传递。
鲍曼不动杆菌(Acinetobacter baumannii)是一种机会性病原体,发病率和死亡率都很高。由于鲍曼不动杆菌对最后一种抗生素的耐药性不断增强,目前针对这种病原体的治疗方案十分有限。尽管鲍曼不动杆菌在世界卫生组织的优先病原体名单中处于领先地位,但人们对它的毒力调节却知之甚少。通过高通量筛选方法鉴定新型生物膜调控因子,我们发现了一种之前未表征的腺苷酸环化酶(AC)CavA,它是这种表型的核心调控因子。我们证实 CavA AC 在鲍曼不动杆菌中具有功能并能合成 cAMP。利用 dRNA-seq 技术,我们验证了 CavA 是一种负面的生物膜形成调节因子,会影响 Csu 绒毛和外多糖的产生。我们首次证明,在鲍曼不动杆菌中,cAMP 是分级信号级联的顶层,它通过调节法定量感应和环状二-GMP 系统控制细菌间和细菌内的信号,最终控制体内毒力和适应性抗生素耐药性。在其他细菌中,cAMP 和环状二-GMP 的水平呈反向调节,而在鲍曼不动杆菌中,这些第二信使的水平成正比。总之,本研究揭示了 CavA 和 cAMP 在鲍曼不动杆菌成功致病过程中的核心作用,并强调了这一信号级联是新疗法开发的潜在靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
PLoS Pathogens
PLoS Pathogens MICROBIOLOGY-PARASITOLOGY
自引率
3.00%
发文量
598
期刊介绍: Bacteria, fungi, parasites, prions and viruses cause a plethora of diseases that have important medical, agricultural, and economic consequences. Moreover, the study of microbes continues to provide novel insights into such fundamental processes as the molecular basis of cellular and organismal function.
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