Whole-Genome Assessment of Clinical Isolates Uncovers Potentially Novel Factors Influencing Carbapenem Resistance.

Carbapenems-one of the important last-line antibiotics for the treatment of gram-negative infections-are becoming ineffective for treating infections. Studies have identified multiple genes (and mechanisms) responsible for carbapenem resistance. In some strains, the presence/absence of putative resistance genes is not consistent with their resistance phenotype-indicating the genomic factors underlying carbapenem resistance in are not fully understood. Here, we describe a large-scale whole-genome genotype-phenotype association study with 349 isolates that extends beyond the presence/absence of individual antimicrobial resistance genes and includes the genomic positions and pairwise interactions of genes. Ten known resistance genes exhibited statistically significant associations with resistance to imipenem, a type of carbapenem: , and . A review of the strains without any of these 10 genes uncovered a clade of isolates with diverse imipenem resistance phenotypes. Finer resolution evaluation of this clade revealed the presence of a 38.6 kbp conserved chromosomal region found exclusively in imipenem-susceptible isolates. This region appears to host several HTH-type DNA binding transcriptional regulators and transporter genes. Imipenem-susceptible isolates from this clade also carried two mutually exclusive plasmids that contain genes previously known to be specific to imipenem-susceptible isolates. Our analysis demonstrates the utility of using whole genomes for genotype-phenotype correlations in the context of antibiotic resistance and provides several new hypotheses for future research.