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Integron gene cassettes harboring novel variants of d-alanine-d-alanine ligase confer high-level resistance to d-cycloserine
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Integron gene cassettes harboring novel variants of d-alanine-d-alanine ligase confer high-level resistance to d-cycloserine
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Integron gene cassettes harboring novel variants of d-alanine-d-alanine ligase confer high-level resistance to d-cycloserine
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Journal Article
Integron gene cassettes harboring novel variants of d-alanine-d-alanine ligase confer high-level resistance to d-cycloserine
2020
Overview
Antibiotic resistance poses an increasing threat to global health. To tackle this problem, the identification of principal reservoirs of antibiotic resistance genes (ARGs) plus an understanding of drivers for their evolutionary selection are important. During a PCR-based screen of ARGs associated with integrons in saliva-derived metagenomic DNA of healthy human volunteers, two novel variants of genes encoding a
d
-alanine-
d
-alanine ligase (
ddl6
and
ddl7
) located within gene cassettes in the first position of a reverse integron were identified.
Treponema denticola
was identified as the likely host of the
ddl
cassettes. Both
ddl6
and
ddl7
conferred high level resistance to
d
-cycloserine when expressed in
Escherichia coli
with
ddl7
conferring four-fold higher resistance to D-cycloserine compared to
ddl6
. A SNP was found to be responsible for this difference in resistance phenotype between the two
ddl
variants. Molecular dynamics simulations were used to explain the mechanism of this phenotypic change at the atomic scale. A hypothesis for the evolutionary selection of
ddl
containing integron gene cassettes is proposed, based on molecular docking of plant metabolites within the ATP and
d
-cycloserine binding pockets of Ddl.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 631/208
/ 631/326
/ Anti-Bacterial Agents - pharmacology
/ Drug Resistance, Bacterial - genetics
/ E coli
/ Escherichia coli - drug effects
/ Genes
/ Humanities and Social Sciences
/ Humans
/ Molecular Docking Simulation
/ Peptide Synthases - genetics
/ Saliva
/ Science
