TY - JOUR
T1 - Genetic determinants underlying the progressive phenotype of β-lactam/β-lactamase inhibitor resistance in Escherichia coli
AU - Shropshire, William C.
AU - Amiji, Hatim
AU - Bremer, Jordan
AU - Selvaraj Anand, Selvalakshmi
AU - Strope, Benjamin
AU - Sahasrabhojane, Pranoti
AU - Gohel, Marc
AU - Aitken, Samuel
AU - Spitznogle, Sarah
AU - Zhan, Xiaowei
AU - Kim, Jiwoong
AU - Greenberg, David E.
AU - Shelburne, Samuel A.
PY - 2023/12/12
Y1 - 2023/12/12
N2 - IMPORTANCE: The increased feasibility of whole-genome sequencing has generated significant interest in using such molecular diagnostic approaches to characterize difficult-to-treat, antimicrobial-resistant (AMR) infections. Nevertheless, there are current limitations in the accurate prediction of AMR phenotypes based on existing AMR gene database approaches, which primarily correlate a phenotype with the presence/absence of a single AMR gene. Our study utilized a large cohort of cephalosporin-susceptible Escherichia coli bacteremia samples to determine how increasing the dosage of narrow-spectrum β-lactamase-encoding genes in conjunction with other diverse β-lactam/β-lactamase inhibitor (BL/BLI) genetic determinants contributes to progressively more severe BL/BLI phenotypes. We were able to characterize the complexity of the genetic mechanisms underlying progressive BL/BLI resistance including the critical role of β-lactamase encoding gene amplification. For the diverse array of AMR phenotypes with complex mechanisms involving multiple genomic factors, our study provides an example of how composite risk scores may improve understanding of AMR genotype/phenotype correlations.
AB - IMPORTANCE: The increased feasibility of whole-genome sequencing has generated significant interest in using such molecular diagnostic approaches to characterize difficult-to-treat, antimicrobial-resistant (AMR) infections. Nevertheless, there are current limitations in the accurate prediction of AMR phenotypes based on existing AMR gene database approaches, which primarily correlate a phenotype with the presence/absence of a single AMR gene. Our study utilized a large cohort of cephalosporin-susceptible Escherichia coli bacteremia samples to determine how increasing the dosage of narrow-spectrum β-lactamase-encoding genes in conjunction with other diverse β-lactam/β-lactamase inhibitor (BL/BLI) genetic determinants contributes to progressively more severe BL/BLI phenotypes. We were able to characterize the complexity of the genetic mechanisms underlying progressive BL/BLI resistance including the critical role of β-lactamase encoding gene amplification. For the diverse array of AMR phenotypes with complex mechanisms involving multiple genomic factors, our study provides an example of how composite risk scores may improve understanding of AMR genotype/phenotype correlations.
KW - AMR gene amplification
KW - BL/BLI
KW - ESRI
KW - progressive AMR resistance
UR - http://www.scopus.com/inward/record.url?scp=85180004900&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85180004900&partnerID=8YFLogxK
U2 - 10.1128/spectrum.02221-23
DO - 10.1128/spectrum.02221-23
M3 - Article
C2 - 37800937
AN - SCOPUS:85180004900
SN - 2165-0497
VL - 11
SP - e0222123
JO - Microbiology Spectrum
JF - Microbiology Spectrum
IS - 6
ER -