Cyclic AMP is a global virulence regulator governing inter and intrabacterial signalling in Acinetobacter baumannii
Year: 2024
Type: article
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.
Source: PLoS Pathogens
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,926
Funders: British Heart Foundation, Diabetes UK, Academy of Medical Sciences, Gottfried Wilhelm Leibniz Universität Hannover, Ministerio de Ciencia e Innovación, Universität zu Köln, Directorate for Biological Sciences, Medical Research Council, Biotechnology and Biological Sciences Research Council, Leibniz-Gemeinschaft, Agencia Estatal de Investigación
Awards: G1405664685, G2253827740, G2262748287, G2660406951, G3480869486, G3518538256, G3875614213, G425668148, Uncovering the antimicrobial and antibiotic potentiating mechanism of acesulfame-K and maximising its topical therapeutic potential., G5421974903, G5805502524, Understanding the molecular survival strategies of Acinetobacter baumannii and developing strategies to disable them., G7084143925, G7734840495
OpenAlex ID: W4402300976