Cyclic Adenosine MonoPhosphate signaling in Mycobacterium abscessus biology and as therapeutic target – MabsCAMP

The MabsCAMP research project aims to investigate the role of cyclic adenosine monophosphate (cAMP) signaling in Mycobacterium abscessus (Mabs), an emerging pathogen causing severe lung infections, particularly in cystic fibrosis (CF) patients. Mabs is notoriously difficult to treat due to its extreme antibiotic resistance, with current treatments lasting for up to two years and having low success rates. Inside the host, Mabs thrives in diverse environments, such as biofilms at the lung epithelium surface or within macrophages, which forces it to adapt its metabolism. These adaptations lead to bacteria displaying phenotypic tolerance to antibiotics (i.e. increased capacity to survive treatment without being resistant), increasing the risk of relapse and emergence of drug resistance.
In several bacterial species, cAMP is a secondary messenger that contributes to biofilm formation and adaptation to stresses, including antibiotics. cAMP is formed from ATP by adenylate cyclases (AC) and is degraded by dedicated phosphodiesterases (PDE). cAMP binds to transcriptional regulators to change gene expression or to enzymes catalyzing post-translational modification on target proteins to modulate their activity. The Mabs genome encodes five AC, one PDE, and at least three cAMP binding proteins. However, the role of cAMP in Mabs remains unknown. MabsCAMP will explore the role of cAMP in Mabs adaptation to the host and to antibiotics.
Four interconnected goals structure the project: i) we aim to map the genes and metabolic pathways controlled by cAMP in Mabs, ii) we will examine the phenotypic consequence of altering cAMP signaling—like biofilm formation, growth and persistence in infectious models, and antibiotic tolerance—; iii) we will characterize the molecular mechanisms driving these changes; iv) we will assess the therapeutic potential of targeting cAMP metabolism to fight Mabs infection.
To achieve these goals, we will implement a large panel of complementary expertises and technologies. First, we will deploy several molecular genetic tools to engineer Mabs mutants with altered cAMP level. Second, we will use various complementary approaches (microbiology, transcriptomic, metabolomic, bioenergetics) to explore in vitro the consequence of cAMP dysregulation on Mabs biology, with a special focus on tolerance to antibiotics, and assess the relevance of targeting cAMP metabolism to fight Mabs. Third, we will implement various complementary infection models, such as human macrophages, airways organoïds derived from CF or non-CF patients, and zebrafish embryos, to explore the impact of cAMP dysregulation on host-pathogen interaction.
This work addresses the global issue of antimicrobial resistance, in the context of an emerging human pathogen. This proposal gathers four internationally-recognized research teams from leading research institutes in France and the UK, with the aim to advance basic science in the biology of bacterial pathogens and to explore novel therapeutic avenues.