Insights into the evolution of the mutational resistome of Pseudomonas aeruginosa in cystic fibrosis

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Chronic respiratory infection (CRI) by Pseudomonas aeruginosa is the main driver of morbidity and mortality in cystic fibrosis (CF) patients [1]. CRI results from an intense adaptation process, where bacterial evolution is tested against host immune responses and years of aggressive antimicrobial treatments [2]. Once established, CRI can seldom be eradicated despite intensive antimicrobial treatments, and therefore our therapeutic goals resignedly move from attempting to cure the infection to minimizing its long-term impact through chronic suppressive therapy [3]. The plasticity of P. aeruginosa genome for antimicrobial resistance acquisition, the greatly enhanced mutation supply rate provided by frequent hypermutable variants (mutators) and the highly structured environment determined by the characteristic biofilm growth and the anatomy of the respiratory tract make bacterial evolution and genetic diversification a hallmark of CF CRI [2,4]. While the enhanced evolution of antimicrobial resistance in CF, frequently linked to mutator phenotypes, was noted many years ago [5], it is with the introduction of whole-genome sequencing (WGS) that we are starting to understand its real dimensions [6].

The term resistome was first used to account for the set of primary antibiotic resistance genes that could be eventually transferred to human pathogens [7]. Soon after the concept of intrinsic resistome was introduced to include all chromosomal genes that are involved in intrinsic resistance, and whose presence in strains of a bacterial species is independent of previous antibiotic exposure and is not due to horizontal gene transfer (HGT) [8]. Finally, the term mutational resistome was more recently implemented to account for the set of mutations involved in the modulation of antibiotic resistance levels in the absence of HGT [9]. Recent WGS data obtained from in vitro assays on the evolution of antibiotic resistance and clinical isolates, and in particular sequential CF isolates, provide new insights into the evolutionary dynamics and mechanisms of P. aeruginosa antibiotic resistance. However, in too many cases, the documented genomic variations fail to provide causative relations in the absence of phenotypic information. The analysis of WGS mutational resistomes has proven to be useful for understanding the evolutionary dynamics of classical resistance mechanisms and to depict new ones for the majority of antimicrobial classes, including β-lactams, aminoglycosides, fluoroquinolones and polymixins.

Read the full article in Future Microbiology here.

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