Antimicrobial Innovations Centre, Division of Biosciences, Department of Life Sciences, College of Health and Life Sciences, Brunel University London, Uxbridge, United Kingdom.
Centro Andaluz de Biología del Desarrollo (CABD-CSIC-JA), Universidad Pablo de Olavide, Sevilla, Spain.
PLoS Pathog. 2024 Sep 6;20(9):e1012529. doi: 10.1371/journal.ppat.1012529. eCollection 2024 Sep.
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.
鲍曼不动杆菌是一种机会性医院获得性病原体，具有较高的发病率和死亡率。由于其对最后一线抗生素的耐药性不断增加，目前针对这种病原体的治疗选择有限。尽管鲍曼不动杆菌在世界卫生组织优先病原体名单中名列前茅，但人们对其毒力调节知之甚少。通过高通量筛选方法来识别新的生物膜调节剂，我们发现了一种以前未被描述的预测腺苷酸环化酶 (AC)，即 CavA，它是这种表型的核心调节剂。cAMP 是其他物种中细菌生理学各个方面的关键介质，但关于其在鲍曼不动杆菌中的作用的信息有限。我们证实 CavA AC 是功能性的，并在鲍曼不动杆菌中合成 cAMP。通过 dRNA-seq，我们验证了 CavA 是一种负性生物膜形成调节剂，影响 Csu 菌毛和外多糖的产生。我们首次证明，在鲍曼不动杆菌中，cAMP 位于一个分层信号级联的顶部，通过调节群体感应和环二鸟苷酸系统来控制细菌间和细菌内信号，最终控制体内毒力和适应性抗生素耐药性。与其他细菌中 cAMP 和环二鸟苷酸水平呈负相关的既定范式相反，我们发现这些第二信使的水平在鲍曼不动杆菌中直接成比例。总的来说，这项研究揭示了 CavA 和 cAMP 在鲍曼不动杆菌致病成功中的核心作用，并强调了这种信号级联作为新型治疗开发的高潜力靶点。
