HIPERMUTABILITY AND THE EVOLUTION OF SMALL COLONY VARIANTS IN Pseudomonas aerginosa BIOFILMS.

SMANIA AM

Paraná

Simposio; LIV Reunión Anual de la Sociedad Argentina de Bioquímica y Biología Molecular; 2018

During chronic lung infections in cystic fibrosis (CF) patients Pseudomonas aeruginosa (PA) grows as biofilm communities, where it undergoes extensive evolutionary diversification. Among the biofilm-adapted specialists, small colony variants (SCVs) are frequently observed, which may associate with worse patient prognosis. SCVs show a great instability when grown outside biofilms, thus revealing the ability to switch between phenotypes. We?ve previously described that hypermutator Mismatch Repair System (MRS)-deficient strains of PA show an increased phenotypic diversification, particularly in biofilms. In this work, we explored the adaptive potential of PA and the role of hypermutability in SCV phenotypic switching by carrying out experimental evolution assays and comparative genomics. Compensatory mutations clustered in pathways related to the synthesis/degradation of the second messenger c-di-GMP in both, wt and mutS hypermutator lines and this parallelism suggests that they evolved through convergent pathways. However, we found that the adaptive potential of hypermutators was notably higher, enabling them to bypass genetic constraints imposed on the successive phenotypic switching. We propose that the limits imposed by the continual SCV bimodal switching are relieved by the existence of multiple loci contributing to control the levels of c-di-GMP, with an enhanced access to these loci enabled by the increased mutation rate. Our results have implications for hypermutator management in clinical settings and may help to better understand the high prevalence of PA isolates exhibiting a hypermutable phenotype in CF chronic pulmonary infections.