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

Kiran Javkar,Nagarajan Thirunavukkarasu,Mihai Pop,Saul Sarria,Hugh Rand,Christine A Pillai,Maria Hoffmann,Patrick Mcgann,Yan Luo,J Kristie Johnson,Errol Strain

doi:10.3389/fmicb.2021.714284

Abstract

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.

Highlights

Antimicrobial resistance (AMR) is a grave healthcare challenge worldwide, causing 700,000 deaths each year (Review on Antimicrobial Resistance, 2016)
The 349 A. baumannii isolates were collected in clinical setting as a part of a surveillance program at the University of Maryland Medical Center (UMMC); these isolates had been sequenced and are accessible through NCBI (Supplementary Table 1)
The level of resistance to several carbapenems was obtained using the Kirby-Bauer disk diffusion method, and phenotypes were determined according to the Clinical Laboratory Standards Institute (CLSI) breakpoints (CDC, 2017)

Summary

Introduction

Antimicrobial resistance (AMR) is a grave healthcare challenge worldwide, causing 700,000 deaths each year (Review on Antimicrobial Resistance, 2016). A sizable proportion of AMR bacterial infections are hospital-acquired and pose a high healthcare burden in developed and developing countries alike (Chen et al, 2015). Some of these bacterial infections can be resistant to even the most powerful antibiotics available; including carbapenems which are typically considered to be one of the “last-line” antibiotics by clinicians, and used in the treatment of critically-ill patients affected potentially by antimicrobial-resistant Gram-negative infections (Codjoe and Donkor, 2017). An increasing rate of carbapenem resistance was documented among A. baumannii strains from numerous hospital outbreaks (Zarrilli et al, 2013; Ben-Chetrit et al, 2018)

Methods

Results

Conclusion