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In vitro resistance development gives insights into molecular resistance mechanisms against cefiderocol
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Journal Article
In vitro resistance development gives insights into molecular resistance mechanisms against cefiderocol
2024
Overview
Cefiderocol, a novel siderophore cephalosporin, demonstrates promising in vitro activity against multidrug-resistant Gram-negative bacteria, including carbapenemase-producing strains. Nonetheless, only a few reports are available regarding the acquisition of resistance in clinical settings, primarily due to its recent usage. This study aimed to investigate cefiderocol resistance using an in vitro resistance development model to gain insights into the underlying molecular resistance mechanisms. Cefiderocol susceptible reference strains (
Escherichia coli
,
Klebsiella pneumoniae
,
Pseudomonas aeruginosa
) and a clinical
Acinetobacter baumannii
complex isolate were exposed to increasing cefiderocol concentrations using a high-throughput resistance development model. Cefiderocol susceptibility testing was performed using broth microdilution. Whole-genome sequencing was employed to identify newly acquired resistance mutations. Our in vitro resistance development model led to several clones of strains exhibiting cefiderocol resistance, with MIC values 8-fold to 512-fold higher than initial levels. In total, we found 42 different mutations in 26 genes, of which 35 could be described for the first time. Putative loss-of-function mutations were detected in the
envZ
,
tonB
, and
cirA
genes in 13 out of 17 isolates, leading to a decrease in cefiderocol influx. Other potential resistance mechanisms included multidrug efflux pumps (
baeS
,
czcS
,
nalC
), antibiotic-inactivating enzymes (
ampR
,
dacB
), and target mutations in penicillin-binding-protein genes (
mrcB
). This study reveals new insights into underlying molecular resistance mechanisms against cefiderocol. While mutations leading to reduced influx via iron transporters was the most frequent resistance mechanism, we also detected several other novel resistance mutations causing cefiderocol resistance.
Publisher
Springer Japan,Nature Publishing Group
Subject
/ 45/23
/ Acinetobacter baumannii - drug effects
/ Acinetobacter baumannii - genetics
/ Anti-Bacterial Agents - pharmacology
/ Bacteria
/ Biomedical and Life Sciences
/ Cephalosporins - pharmacology
/ Drug Resistance, Bacterial - genetics
/ Drug Resistance, Multiple, Bacterial - genetics
/ E coli
/ Efflux
/ Escherichia coli - drug effects
/ Genes
/ Humans
/ Klebsiella pneumoniae - drug effects
/ Klebsiella pneumoniae - genetics
/ Mutation
/ Pseudomonas aeruginosa - drug effects
