Network-level divergence in cyclic di-GMP signalling drives ecological versatility in Acinetobacter baumannii.

Second messenger signalling pathways are known to play a fundamental role in governing bacterial physiology and mediating rapid adaptive responses to stimuli. Despite the extensive characterisation of second messenger signalling systems such as the cyclic di-GMP (c-di-GMP) signalling system in pathogens, relatively little is known about the role of these pathways in the priority pathogen Acinetobacter baumannii. To address this, we carried out a comprehensive exploration of c-di-GMP signalling across multiple modern A. baumannii clinical isolates. We elucidate this second messenger's regulon and its role in biofilm formation and other virulence-associated behaviours. Furthermore, we demonstrate that specific enzymes controlling c-di-GMP levels are associated with specific international clones, with PdeD being identified as the primary functional phosphodiesterase in the worldwide prevalent International Clone I. Further characterisation of PdeD revealed it as a key regulatory node, controlling host colonisation in a murine model and persistence in the hospital environment. This indicates that the physiological control exerted by PdeD represented a distinctive advantage for the global dissemination of this lineage. Overall, this work uncovers the core regulatory role of c-di-GMP in underpinning the recalcitrant pathobiology of A. baumannii and also reveals PdeD as a potential novel therapeutic target.