Abstract
Although the failure of antibiotic treatment is normally attributed to resistance, tolerance and persistence display a significant role in the lack of response to antibiotics. Due to the fact that several nosocomial pathogens show a high level of tolerance and/or resistance to chlorhexidine, in this study we analyzed the molecular mechanisms associated with chlorhexidine adaptation in two clinical strains of Klebsiella pneumoniae by phenotypic and transcriptomic studies. These two strains belong to ST258-KPC3 (high-risk clone carrying β-lactamase KPC3) and ST846-OXA48 (low-risk clone carrying β-lactamase OXA48). Our results showed that the K. pneumoniae ST258-KPC3CA and ST846-OXA48CA strains exhibited a different behavior under chlorhexidine (CHLX) pressure, adapting to this biocide through resistance and tolerance mechanisms, respectively. Furthermore, the appearance of cross-resistance to colistin was observed in the ST846-OXA48CA strain (tolerant to CHLX), using the broth microdilution method. Interestingly, this ST846-OXA48CA isolate contained a plasmid that encodes a novel type II toxin/antitoxin (TA) system, PemI/PemK. We characterized this PemI/PemK TA system by cloning both genes into the IPTG-inducible pCA24N plasmid, and found their role in persistence and biofilm formation. Accordingly, the ST846-OXA48CA strain showed a persistence biphasic curve in the presence of a chlorhexidine-imipenem combination, and these results were confirmed by the enzymatic assay (WST-1).
Highlights
The increase in antimicrobial resistance due to the emergence of multi-drug resistant (MDR)pathogens is one of the world’s greatest public health challenges, as it can lead to an era without effective antibiotics [1]
This study provides a better comprehension of the molecular mechanisms associated with chlorhexidine adaptation (CA) in two clinical strains of K. pneumoniae, both of which produce carbapenemase: ST258-KPC3 and ST846-OXA48, from a phenotypic and transcriptomic point of view
This slight reduction in the bacterial population occurs during the activation of defense mechanisms, such as efflux pumps, which can reduce the effective concentration of the drug in the cell
Summary
The increase in antimicrobial resistance due to the emergence of multi-drug resistant (MDR)pathogens is one of the world’s greatest public health challenges, as it can lead to an era without effective antibiotics [1]. The World Health Organization (WHO) published a list of “priority pathogens”, which includes those microorganisms considered a serious threat to human health. Some members of this list are carbapenem-resistant pathogens and are known under the acronym of ESKAPE, including among other species, Klebsiella pneumoniae [1,2,3]. Carbapenem resistance is increasing rapidly worldwide, among K. pneumoniae. The main carbapenem-resistance mechanism is acquisition of plasmid-encoded carbapenemases, which may belong to the molecular class A (i.e., KPCtype), B (i.e., imipenem (IMP)-type, VIM-type, NDM-type) and D (i.e., OXA-48-type). The high-risk clones of K. pneumoniae, in contrast to low-risk clones, have an extraordinary ability to persist and spread in the nosocomial environment, disseminating these carbapenemases and being involved in nosocomial outbreaks [4]
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