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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.

Integron gene cassettes harboring novel variants of d-alanine-d-alanine ligase confer high-level resistance to d-cycloserine