An Evaluation of BfmR-Regulated Antimicrobial Resistance in the Extensively Drug Resistant (XDR) Acinetobacter baumannii Strain HUMC1

Abstract

Acinetobacter baumannii is a problematic pathogen due to its common expression of extensive drug resistance (XDR) and ability to survive in the healthcare environment. These characteristics are mediated, in part, by the signal transduction system BfmR/BfmS. We previously demonstrated, in antimicrobial sensitive clinical isolates, that BfmR conferred increased resistance to meropenem and polymyxin E. In this study, potential mechanisms were informed, in part, by a prior transcriptome analysis of the antimicrobial sensitive isolate AB307-0294, which identified the porins OprB and aquaporin (Omp33-36, MapA) as plausible mediators for resistance to hydrophilic antimicrobials such as meropenem. Studies were then performed in the XDR isolate HUMC1, since delineating resistance mechanisms in this genomic background would be more translationally relevant. In HUMC1 BfmR likewise increased meropenem and polymyxin E resistance and upregulated gene expression of OprB and aquaporin. However, the comparison of HUMC1 with isogenic mutant constructs demonstrated that neither OprB nor aquaporin affected meropenem resistance; polymyxin E susceptibility was also unaffected. Next, we determined whether BfmR-mediated biofilm production affected either meropenem or polymyxin E susceptibilities. Interestingly, biofilm formation increased resistance to polymyxin E, but had little, if any effect on meropenem activity. Additionally, BfmR mediated meropenem resistance, and perhaps polymyxin E resistance, was due to BfmR regulated factors that do not affect biofilm formation. These findings increase our understanding of the mechanisms by which BfmR mediates intrinsic antimicrobial resistance in a clinically relevant XDR isolate and suggest that the efficacy of different classes of antimicrobials may vary under biofilm inducing conditions.

Acinetobacter baumannii Regulates Its Stress Responses via the BfmRS Two-Component Regulatory System

“…Similarly, both BfmR and BfmS mutations reduced A. baumannii's survival in a murine pneumonia model (28). BfmR and BfmS have also been implicated in controlling resistance to a variety of antibiotics, including penicillins, carbapenems, fluoroquinolones, aminoglycosides, and macrolides (20,25,29,30). Finally, we previously found that BfmR is required for A. baumannii to endure a variety of stresses, including desiccation, osmotic challenge, exposure to hydrogen peroxide, and starvation (31).…”

Whole-Genome Sequencing of ST2 A. baumannii Causing Bloodstream Infections in COVID-19 Patients

“…The pathogenicity of A. baumannii isolates analyzed in the present study is exacerbated by the presence of the abaI / abaR quorum sensing system which is involved in morphology, growth characteristics, biofilm formation, motility, resistance and virulence of these microorganisms [ 36 ]. In addition, in our A. baumannii we found two-component signal transduction system BfmRS , which seem to be implicated in the control of various virulence-related traits and acting as a global modulator of A. baumannii physiology [ 37 , 38 ]. It is well known that, A. baumannii showing a loss of BfmS results in a significant reduction of motility [ 39 ].…”

Repurposed dihydroorotate dehydrogenase inhibitors with efficacy against drug-resistant Acinetobacter baumannii

“…MIC was also determined by measuring CFUs in wells at 24 h; the MIC as assessed by CFU was designated as the drug concentration that inhibited growth ± ½ log relative to the starting inoculum when measured at 24 h. Doses ranged from 0.050 µM to 50 µM for DSM161 and from 0.010 µM to 13 µM for DSM186. Time-kill assays were performed in the presence or absence of a fixed DSM drug concentration (DSM161 50 µM (17.5 µg/mL), DSM186 2.9 µM (1 µg/mL)) over time as described ( 44 ) and compared to meropenem 2.6 µM (1 µg/mL).…”