Journal
FRONTIERS IN MICROBIOLOGY
Volume 12, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fmicb.2021.714284
Keywords
whole-genome comparison; antibiotic resistance; genomic association studies; multiple genome alignment; Acinetobacter baumanni
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Funding
- University of Maryland, Joint Institute for Food Safety and Applied Nutrition (JIFSAN) [5U01-FD001418]
- U.S. Food and Drug Administration, Center for Food Safety and Applied Nutrition (FDA, CFSAN)
- NIH [R01-AI-100947]
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This large-scale whole-genome genotype-phenotype association study on 349 A. baumannii isolates identified 10 known resistance genes significantly associated with resistance to imipenem and revealed a conserved chromosomal region exclusive to imipenem-susceptible isolates. These findings provide new hypotheses for future research in understanding the genetic factors underlying carbapenem resistance in A. baumannii.
Carbapenems-one of the important last-line antibiotics for the treatment of gram-negative infections-are becoming ineffective for treating Acinetobacter baumannii infections. Studies have identified multiple genes (and mechanisms) responsible for carbapenem resistance. In some A. baumannii strains, the presence/absence of putative resistance genes is not consistent with their resistance phenotype-indicating the genomic factors underlying carbapenem resistance in A. baumannii are not fully understood. Here, we describe a large-scale whole-genome genotype-phenotype association study with 349 A. baumannii 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: blaOXA-23, qacEdelta1, sul1, mphE, msrE, ant(3)-II, aacC1, yafP, aphA6, and xerD. 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.
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