Colistin Resistance Onset Strategies and Genomic Mosaicism in Clinical Acinetobacter baumannii Lineages

Abstract

The treatment of multidrug-resistant Gram-negative infections is based on colistin. As result, COL-resistance (COL-R) can develop and spread. In Acinetobacter baumannii, a crucial step is to understand COL-R onset and stability, still far to be elucidated. COL-R phenotypic stability, onset modalities, and phylogenomics were investigated in a clinical A. baumannii sample showing a COL resistant (COLR) phenotype at first isolation. COL-R was confirmed by Minimum-Inhibitory-Concentrations as well as investigated by Resistance-Induction assays and Population-Analysis-Profiles (PAPs) to determine: (i) stability; (ii) inducibility; (iii) heteroresistance. Genomics was performed by Mi-Seq Whole-Genome-Sequencing, Phylogenesis, and Genomic Epidemiology by bioinformatics. COLRA. baumannii were subdivided as follows: (i) 3 A. baumannii with stable and high COL MICs defining the “homogeneous-resistant” onset phenotype; (ii) 6 A. baumannii with variable and lower COL MICs displaying a “COL-inducible” onset phenotype responsible for adaptive-resistance or a “subpopulation” onset phenotype responsible for COL-heteroresistance. COL-R stability and onset strategies were not uniquely linked to the amount of LPS and cell envelope charge. Phylogenomics categorized 3 lineages clustering stable and/or unstable COL-R phenotypes with increasing genomic complexity. Likewise, different nsSNP profiling in genes already associated with COL-R marked the stable and/or unstable COL-R phenotypes. Our investigation finds out that A. baumannii can range through unstable or stable COLR phenotypes emerging via different “onset strategies” within phylogenetic lineages displaying increasing genomic mosaicism.

Acinetobacter baumannii and Cefiderocol, between Cidality and Adaptability

“… Acinetobacter baumannii is a major clinical threat, both because of its established role as an important pathogen associated with nosocomial infections at various body sites and because of the challenge posed by the very limited treatment options available, due to its high intrinsic and acquired antimicrobial resistance. The latter entails, in many cases and for different antibiotics, characteristics of instability, related to frequent genomic rearrangements involving gene amplification, mobile genetic element (MGE) acquisition, and resistome and phage profile changes, as recently demonstrated ( 1 , 2 ).…”

Editorial on the Research Topic of the Special Issue “Current Status of Acinetobacter Infections”

“…Specifically, the knowledge of antimicrobial resistance gene acquisition, genomic mutations, or modifications in the expression of some genes plays a key role in the therapeutic success against multidrug-resistant (MDR) A. baumannii infections [ 9 ]. About this, the investigation of Cafiso et al [ 10 ], in this Special Issue, on phenotypic and genomic characterization as well as on phylogenetic relationship in A. baumannii samples, showed different levels of colistin resistance (COL-R) and heteroresistance, suggesting more strategies that A. baumannii can use to become resistant. This leads to the strain definition as unstable or stable colistin-resistant and overall, to the so-called dynamism hypothesis of the COL-R stability acquisition.…”

Acinetobacter baumannii and cefiderocol between cidality and adaptability

“…Acinetobacter baumannii is a major clinical threat, both because of its established role as an important pathogen associated with nosocomial infections at various body sites and the challenge posed by the very limited treatment options available, due to its high intrinsic and acquired antimicrobial resistance. The latter entails, in many cases and for different antibiotics, characteristics of instability, related - as recently demonstrated – to frequent genomic rearrangements involving gene amplification, MGE acquisition, resistome and phage profiling changes [1,2].…”