Abstract
Infections caused by multidrug resistant (MDR) bacteria are a major concern worldwide. Changes in membrane permeability, including decreased influx and/or increased efflux of antibiotics, are known as key contributors of bacterial MDR. Therefore, it is of critical importance to understand molecular mechanisms that link membrane permeability to MDR in order to design new antimicrobial strategies. In this work, we describe genotype-phenotype correlations in Enterobacter aerogenes, a clinically problematic and antibiotic resistant bacterium. To do this, series of clinical isolates have been periodically collected from two patients during chemotherapy with imipenem. The isolates exhibited different levels of resistance towards multiple classes of antibiotics, consistently with the presence or the absence of porins and efflux pumps. Transport assays were used to characterize membrane permeability defects. Simultaneous genome-wide analysis allowed the identification of putative mutations responsible for MDR. The genome of the imipenem-susceptible isolate G7 was sequenced to closure and used as a reference for comparative genomics. This approach uncovered several loci that were specifically mutated in MDR isolates and whose products are known to control membrane permeability. These were omp35 and omp36, encoding the two major porins; rob, encoding a global AraC-type transcriptional activator; cpxA, phoQ and pmrB, encoding sensor kinases of the CpxRA, PhoPQ and PmrAB two-component regulatory systems, respectively. This report provides a comprehensive analysis of membrane alterations relative to mutational steps in the evolution of MDR of a recognized nosocomial pathogen.
Highlights
Multidrug resistance (MDR) is a significant problem for treatment of bacterial infections worldwide
Isolate P1 corresponded to the first isolation of E. aerogenes from a bronchial aspirate and was susceptible to almost all tested antibiotics including gentamicin, carbapenems, third and fourth generation cephalosporins, and quinolones (Table 1 and S1 Table for detailed Minimal inhibitory concentrations (MICs) values)
A first step to combat this threat is to understand the genomic traits of resistant clinical isolates as a mean to get new insight into their successful adaptation as nosocomial pathogens
Summary
Multidrug resistance (MDR) is a significant problem for treatment of bacterial infections worldwide. Changes in the bacterial cell envelope are a key contributor to the high levels of resistance towards β-lactams, including carbapenems, and other antibiotic families such as fluoroquinolones [6,7,8,9,10, 12, 15,16,17,18] These changes include quantitative or qualitative modifications of outer membrane porins [6,7,8,9,10, 16, 18,19,20], and increased levels of efflux pumps [12, 17, 18, 21, 22]. Imipenem and others effectors probably act by activating MDR regulators such as MarA or RamA
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