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.
Highlights
Acinetobacter baumannii is a nosocomial pathogen that has plagued healthcare facilities by its capacity to survive for prolonged periods on abiotic surfaces and express extensive drug resistance (XDR)
To confirm an effect of BfmR on increasing resistance to meropenem and polymyxin E (Russo et al, 2016; Geisinger et al, 2018) in the XDR A. baumannii strain HUMC1, the isogenic mutant construct HUMC1 bfmR was generated for comparison with its wild-type parent
HUMC1 bfmR demonstrated a significantly increased susceptibility to meropenem and polymyxin E when assessed in CAMH (Figure 1)
Summary
Acinetobacter baumannii is a nosocomial pathogen that has plagued healthcare facilities by its capacity to survive for prolonged periods on abiotic surfaces and express extensive drug resistance (XDR) This ability is, in part, mediated by the two-component sensor/response signal transduction system BfmS/BfmR. An important step for translating these data into clinical practice is the delineation of the relative roles of BfmR-regulated gene products in conferring resistance. A bioinformatics analysis and expression levels were used to filter putative gene products that could contribute to BfmR-regulated antimicrobial resistance to meropenem and polymyxin E These data served as a starting point to identify potential contributory genes in an XDR isolate since for the optimal translation of preclinical data, it is important to study clinical strains with the greatest translational impact (Russo et al, 2016; Wong et al, 2017). The hypothesis that BfmR mediated biofilm production contributed to the phenotype of carbapenem and polymyxin resistance in the XDR strain HUMC1 was assessed
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