Chromosomal mechanisms of aminoglycoside resistance in Pseudomonas aeruginosa isolates from cystic fibrosis patients

Islam, Sohidul; Oh, Hyemin; Jalal, Shah; Karpati, Ferenc; Ciofu, Oana; Høiby, Niels; Wretlind, Bengt

doi:10.1111/j.1469-0691.2008.02097.x

Cited by 75 publications

(59 citation statements)

References 25 publications

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“…Contrary to what we observed in the acrB mutant, Pérez et al showed modest decreases in the MICs of aminoglycosides in the acrA mutant of E. cloacae (27). It has been reported that the overexpression of MexY correlated with decreased susceptibility to aminoglycosides of P. aeruginosa and that the RND protein AdeB of Acinetobacter baumannii was responsible for aminoglycoside resistance (40,41). Interestingly, ECL_01758 was found to be the polypeptide most homologous to AdeB (58% identity and 76% similarity).…”

Section: Resultscontrasting

confidence: 49%

Landscape of Resistance-Nodulation-Cell Division (RND)-Type Efflux Pumps in Enterobacter cloacae Complex

Guérin

Lallement

Isnard

et al. 2016

Antimicrob Agents Chemother

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cIn Gram-negative bacteria, the active efflux is an important mechanism of antimicrobial resistance, but little is known about the Enterobacter cloacae complex (ECC). It is mediated primarily by pumps belonging to the RND (resistance-nodulation-cell division) family, and only AcrB, part of the AcrAB-TolC tripartite system, was characterized in ECC. However, detailed genome sequence analysis of the strain E. cloacae subsp. cloacae ATCC 13047 revealed to us that 10 other genes putatively coded for RNDtype transporters. We then characterized the role of all of these candidates by construction of corresponding deletion mutants, which were tested for their antimicrobial susceptibility to 36 compounds, their virulence in the invertebrate Galleria mellonella model of infection, and their ability to form biofilm. Only the ⌬acrB mutant displayed significantly different phenotypes compared to that of the wild-type strain: 4-to 32-fold decrease of MICs of several antibiotics, antiseptics, and dyes, increased production of biofilm, and attenuated virulence in G. mellonella. In order to identify specific substrates of each pump, we individually expressed in trans all operons containing an RND pump-encoding gene into the ⌬acrB hypersusceptible strain. We showed that three other RND-type efflux systems (ECL_00053-00055, ECL_01758-01759, and ECL_02124-02125) were able to partially restore the wild-type phenotype and to superadd to and even enlarge the broad range of antimicrobial resistance. This is the first global study assessing the role of all RND efflux pumps chromosomally encoded by the ECC, which confirms the major role of AcrB in both pathogenicity and resistance and the potential involvement of other RND-type members in acquired resistance.

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Section: Resultscontrasting

confidence: 49%

Landscape of Resistance-Nodulation-Cell Division (RND)-Type Efflux Pumps in Enterobacter cloacae Complex

Guérin

Lallement

Isnard

et al. 2016

Antimicrob Agents Chemother

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“…However, the ⌬mexXY strain actually grows slightly faster than the parent isolate ( Table 1). The MexXYOprM pump is especially effective in extruding aminoglycosides (27), and the 96-month isolate is resistant to tobramycin, with a MIC 32 times higher than that of the parent strain ( Table 1). The parent strain was rapidly killed by tobramycin at the stationary phase, with little evidence for surviving persisters (Fig.…”

Section: Resultsmentioning

confidence: 99%

Emergence of Pseudomonas aeruginosa Strains Producing High Levels of Persister Cells in Patients with Cystic Fibrosis

et al. 2010

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The majority of cystic fibrosis (CF) patients succumb to a chronic infection of the airway with Pseudomonas aeruginosa. Paradoxically, pathogenic strains are often susceptible to antibiotics, but the infection cannot be eradicated with antimicrobial therapy. We find that in a majority of patients with airway infections, late isolates of P. aeruginosa produce increased levels of drug-tolerant persister cells. The genomes of a clonal pair of early/late isolates from a single patient have been previously sequenced, and the late isolate (obtained at age 96 months) showed a 100-fold increase in persister levels. The 96-month isolate carries a large number of mutations, including a mutation in mutS that confers a hypermutator phenotype. There is also a mutation in the mexZ repressor controlling the expression of the MexXY-OprM multidrug pump, which results in a moderate increase in the ofloxacin, carbenicillin, and tobramycin MICs. Knocking out the mexXY locus restored the resistance to that of the parent strain but did not affect the high levels of persisters formed by the 96-month isolate. This suggests that the late isolate is a high-persister (hip) mutant. Increased persister formation was observed in exponential phase, stationary phase, and biofilm populations of the 96-month isolate. Analysis of late isolates from 14 additional patients indicated that 10 of them are hip mutants. Most of these hip mutants did not have higher drug resistance. Increased persister formation appears to be their sole mechanism for surviving chemotherapy. Taken together, these findings suggest a link between persisters and recalcitrance of CF infection and identify an overlooked culprit-high-persister mutants producing elevated levels of drugtolerant cells. Persisters may play a similarly critical role in the recalcitrance of other chronic infections.The majority of cystic fibrosis (CF) patients succumb to a chronic untreatable Pseudomonas aeruginosa infection of the airways (18). The strains responsible for these infections are largely clonal and show evidence of positive selection for mutations leading to adaptation to the airway environment (39). Mutants of P. aeruginosa resistant to antibiotics are selected in CF patients, which can contribute to therapy failure. These include overexpression of multidrug resistance pumps, target modification, and plasmid-mediated resistance (18). It is important to note, however, that isolates of P. aeruginosa from CF patients do not necessarily develop high-level antibiotic resistance (4,19,21). This creates a paradox: antibiotics that are effective in inhibiting the growth of the pathogen in vitro are unable to cure the infection. We suggested that persister cells are responsible for maintaining untreatable infections (36). Persisters are dormant phenotypic variants rather than mutants and have been produced by all microbial pathogens studied to date (28,34,44,48). Persisters make up a small fraction of the population but are the only cells to survive treatment with high doses of bactericidal ant...

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“…For aminoglycosides, the higher potency of tobramycin over amikacin in our collection also reflects what is observed in MIC distributions of wild-type strains assembled by EUCAST (29). Tobramycin has been described as a poorer substrate than amikacin for the efflux pump MexXY-OprM, considered responsible for natural and adaptive resistance to aminoglycosides in P. aeruginosa (36,37).…”

Section: Discussionmentioning

confidence: 99%

Antimicrobial Susceptibility of Pseudomonas aeruginosa Isolated from Cystic Fibrosis Patients in Northern Europe

Mustafa

Chalhoub

Denis

et al. 2016

Antimicrob Agents Chemother

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f Pseudomonas aeruginosa is a major cause of morbidity and mortality in cystic fibrosis patients. This study compared the antimicrobial susceptibilities of 153 P. aeruginosa isolates from the United Kingdom (UK) (n ‫؍‬ 58), Belgium (n ‫؍‬ 44), and Germany (n ‫؍‬ 51) collected from 118 patients during routine visits over the period from 2006 to 2012. MICs were measured by broth microdilution. Genes encoding extended-spectrum ␤-lactamases (ESBL), metallo-␤-lactamases, and carbapenemases were detected by PCR. Pulsed-field gel electrophoresis and multilocus sequence typing were performed on isolates resistant to >3 antibiotic classes among the penicillins/cephalosporins, carbapenems, fluoroquinolones, aminoglycosides, and polymyxins. Based on EUCAST/CLSI breakpoints, susceptibility rates were <30%/<40% (penicillins, ceftazidime, amikacin, and ciprofloxacin), 44 to 48%/48 to 63% (carbapenems), 72%/72% (tobramycin), and 92%/78% (colistin) independent of patient age. Sixty percent of strains were multidrug resistant (MDR; European Centre for Disease Prevention and Control criteria). Genes encoding the most prevalent ESBL (BEL, PER, GES, VEB, CTX-M, TEM, SHV, and OXA), metallo-␤-lactamases (VIM, IMP, and NDM), or carbapenemases (OXA-48 and KPC) were not detected. The Liverpool epidemic strain (LES) was prevalent in UK isolates only (75% of MDR isolates). Four MDR sequence type 958 (ST958) isolates were found to be spread over the three countries. The other MDR clones were evidenced in <3 isolates and localized in a single country. A new sequence type (ST2254) was discovered in one MDR isolate in Germany. Clonal and nonclonal isolates with different susceptibility profiles were found in 20 patients. Thus, resistance and MDR are highly prevalent in routine isolates from 3 countries, with meropenem, tobramycin, and colistin remaining the most active drugs.

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Chromosomal mechanisms of aminoglycoside resistance in Pseudomonas aeruginosa isolates from cystic fibrosis patients

Cited by 75 publications

References 25 publications

Landscape of Resistance-Nodulation-Cell Division (RND)-Type Efflux Pumps in Enterobacter cloacae Complex

Landscape of Resistance-Nodulation-Cell Division (RND)-Type Efflux Pumps in Enterobacter cloacae Complex

Emergence of Pseudomonas aeruginosa Strains Producing High Levels of Persister Cells in Patients with Cystic Fibrosis

Antimicrobial Susceptibility of Pseudomonas aeruginosa Isolated from Cystic Fibrosis Patients in Northern Europe

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