| Autor: |
Khondaker M. Rahman, Peter Mullany, Md. Ajijur Rahman, Adam P. Roberts, Shirin Jamshidi, Frank Kaiser |
| Rok vydání: |
2020 |
| Předmět: |
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| DOI: |
10.1101/2020.05.09.085589 |
| Popis: |
During a PCR-based screen of antibiotic resistance genes (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 (ddl6andddl7) located within gene cassettes in the first position of a reverse integron were identified.Treponema denticolawas identified as the likely host of theddlcassettes. Bothddl6andddl7conferred high level resistance to D-cycloserine when expressed inEscherichia coliwithddl7conferring four-fold higher resistance to D-cycloserine compared toddl6. A SNP was found to be responsible for this difference in resistance phenotype between bothddlvariants. Molecular dynamics simulations were used to explain the mechanism of this phenotypic change at the atomic scale. A hypothesis for the evolutionary selection ofddlcontaining integron gene cassettes is proposed, based on molecular docking of plant metabolites within the ATP and D-cycloserine binding pockets of Ddl.Significance StatementThe drivers of antimicrobial resistance are varied and numerous. One such hypothesis is that compounds not normally considered to be antibiotics may be able to select for genes that can provide resistance to conventional antibiotics. Here we provide evidence that dietary flavonoids are likely to provide the selective pressure for two novel variants of theddlgene, encoding D-alanine-D-alanine ligases, to be maintained as the first gene cassette of a reverse integron detectable in the human oral cavities from both the UK and Bangladesh. We show that Ddl is functional, able to confer resistance to D-cycloserine and that the dietary flavonoids quercetin and apigenin are likely able to compete with both ATP and D-cycloserine within their Ddl binding sites. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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