The AcrAB-TolC Pump Is Involved in Macrolide Resistance but Not in Telithromycin Efflux in<i>Enterobacter aerogenes</i>and<i>Escherichia coli</i>

Chollet, Renaud; Chevalier, Jacqueline; Bryskier, A.; Pagès, Jean‐Marie

doi:10.1128/aac.48.9.3621-3624.2004

Cited by 96 publications

(75 citation statements)

References 25 publications

(36 reference statements)

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“…The current information on these systems is limited to efflux pumps in which the effects on macrolides have been tested and efflux pumps do not necessarily extrude related antibacterial agents with the same efficacy (Chollet et al, 2004). Thus, the information available on efflux systems is incomplete, albeit growing rapidly.…”

Section: Chromosomal Efflux Pumpsmentioning

confidence: 99%

“…These observations are consistent with the aforementioned effect of the PAbN (Gomes et al, 2013b) and with the 128-fold decreases in the MIC levels to erythromycin, clarithromycin and azithromycin (from 512 mg/L to 4 mg/L for the first two and from 64 to 0.5 for azithromycin) described by Wehmeier et al (2009) when disrupting the acrB gene. As with other antimicrobial families, this kind of generic efflux pumps are not able to extrude all macrolide members from the bacterial cytoplasm, thereby demonstrating the inability of AcrAB-TolC to pump out telithromycin (Chollet et al, 2004). In addition to the expression levels, the presence of specific amino acid changes in AcrAB-TolC may result in differences in macrolide-affinity, leading to differences in the final MIC levels (Wehmeier et al, 2009).…”

Section: Chromosomal Efflux Pumpsmentioning

confidence: 99%

See 1 more Smart Citation

Macrolide resistance mechanisms inEnterobacteriaceae: Focus on azithromycin

Gomes

Martínez-Puchol

Palma

et al. 2016

Critical Reviews in Microbiology

116

120

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Section: Chromosomal Efflux Pumpsmentioning

confidence: 99%

Section: Chromosomal Efflux Pumpsmentioning

confidence: 99%

Macrolide resistance mechanisms inEnterobacteriaceae: Focus on azithromycin

Gomes

Martínez-Puchol

Palma

et al. 2016

Critical Reviews in Microbiology

116

120

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“…Efflux pumps can dramatically alter the sensitivity of bacteria to antibiotics (2). For example, phenylanine-arginine-␤-napthylamide (PA␤N) inhibits multidrug efflux pumps and markedly lowers the MIC of erythromycin and other antibiotics (25,26). In strains expressing only L22-titin or only ⌬MKR-L22-titin, 30 g/ml PA␤N lowered the MIC for erythromycin Ͼ20-fold (Fig.…”

Section: ⌬Mkr Ribosomes Are Inhibited By Erythromycin In Vitromentioning

confidence: 99%

Revisiting the mechanism of macrolide-antibiotic resistance mediated by ribosomal protein L22

Moore

Sauer²

2008

Proc. Natl. Acad. Sci. U.S.A.

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Bacterial antibiotic resistance can occur by many mechanisms. An intriguing class of mutants is resistant to macrolide antibiotics even though these drugs still bind to their targets. For example, a 3-residue deletion (⌬MKR) in ribosomal protein L22 distorts a loop that forms a constriction in the ribosome exit tunnel, apparently allowing nascent-chain egress and translation in the presence of bound macrolides. Here, however, we demonstrate that ⌬MKR and wild-type ribosomes show comparable macrolide sensitivity in vitro. In Escherichia coli, we find that this mutation reduces antibiotic occupancy of the target site on ribosomes in a manner largely dependent on the AcrAB-TolC efflux system. We propose a model for antibiotic resistance in which ⌬MKR ribosomes alter the translation of specific proteins, possibly via changes in programmed stalling, and modify the cell envelope in a manner that lowers steady-state macrolide levels.ermC ͉ erythromycin ͉ ribosome ͉ TolC M any antibiotics inhibit bacterial protein synthesis. Understanding how microbes become antibiotic resistant is important both for developing effective treatment regimens and designing new therapeutics. Macrolides consist of a 14-to 16-member lactone ring with different appended sugars and comprise a key group of inhibitors of bacterial translation (1, 2). The inhibitory activity of macrolides, including erythromycin, depends on binding to a site near the polypeptide exit tunnel of the large ribosomal subunit (3, 4). Because macrolides do not bind to ribosomes with an occupied exit tunnel and cause the synthesis of 2-10 residue peptides in translation assays in vitro, it has been proposed that drug binding physically blocks elongation of nascent proteins beyond this size (5-7).Some macrolide-resistance mutations alter the ribosomal target site and prevent binding (4,8). Intriguingly, other mutations confer resistance despite the fact that macrolides still bind the mutant ribosome well (8-10). For example, deletion of the M 82 K 83 R 84 sequence in Escherichia coli ribosomal protein L22 (⌬MKR) allows growth in the presence of high levels of erythromycin and other macrolides (11-13). The same mutation makes Haemophilus influenzae resistant to numerous macrolides (14); different L22 mutations also confer macrolide resistance in other bacterial species (2). When binding has been measured, ribosomes with macrolideresistant alterations in L22 bind erythromycin with near wild-type affinity (8,10,12,15).In a crystal structure of the E. coli ribosome, the MKR sequence is part of an extended L22 loop, which together with a similar loop in protein L4 forms a narrow constriction in the exit tunnel (Fig. 1A) (16, 17). Cryo-EM studies initially revealed a widened exit tunnel in E. coli ⌬MKR ribosomes (18). This loop is also displaced to create an expanded tunnel in structures of ⌬MKR ribosomes from Thermus thermophilus and Haloarcula marismortui (4, 19). These results explain the altered chemical reactivity in E. coli ⌬MKR ribosomes of 23S-RNA bases (13). Together,...

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“…Hence, the bacteria become insensitive to antibiotics. Several methods have been used to measure EP system activity, such as an ethidium bromide (EtBr) accumulation assay (Paixão et al, 2009), an EP inhibition assay (Chollet et al, 2004), radiolabelled antibiotics (Hasdemir et al, 2004), and other methods (Daugelavičius et al, 2010). The most commonly used method is the EtBr accumulation assay, which is based on monitoring the accumulation of the fluorescent probe, EtBr (Paixão et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Influence of induced ciprofloxacin resistance on efflux pump activity of Klebsiella pneumoniae

Zhong

Zhang

Pan

et al. 2013

J. Zhejiang Univ. Sci. B

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Abstract:Objective: The efflux pump (EP) is one of the major mechanisms of antibiotic resistance in Klebsiella pneumoniae. However, there are few reports on the effect of the abuse of antibiotic use on the activity of EPs. To determine whether the use of low efficacy antibiotics has any effect on the activity of EPs and induces drug resistance in K. pneumoniae, we investigated the effect of ciprofloxacin on the activity of EPs in K. pneumoniae strains. Methods: Sixteen susceptible K. pneumoniae strains were isolated from patients and their minimum inhibitory concentrations (MICs) of ciprofloxacin were measured in the absence and presence of the pump inhibitor carbonyl cyanide m-chlorophenyl hydrazone (CCCP). The strains were then induced with a gradient of ciprofloxacin until the MICs of the strains showed no further increase, to obtain induced resistant strains. The EP activities of the strains before and after induction were compared using EP inhibition and ethidium bromide (EtBr) accumulation assays. Results: The MIC values of the strains were 16-256 times higher after induction than before induction. In the presence of CCCP, the MIC values of 50% of the induced strains were 2-4-fold lower than that in the absence of this inhibitor. The EtBr accumulation assay showed that the fluorescence of EtBr in the induced cells was lower than that in the cells before induction. Conclusions: EPs are widespread in susceptible and drug-resistant K. pneumoniae strains. Induction with ciprofloxacin may increase the activity of EPs in K. pneumoniae. The EtBr accumulation assay is more sensitive than the EP inhibition assay in evaluating the activity of EPs in K. pneumoniae.

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The AcrAB-TolC Pump Is Involved in Macrolide Resistance but Not in Telithromycin Efflux inEnterobacter aerogenesandEscherichia coli

Cited by 96 publications

References 25 publications

Macrolide resistance mechanisms inEnterobacteriaceae: Focus on azithromycin

Macrolide resistance mechanisms inEnterobacteriaceae: Focus on azithromycin

Revisiting the mechanism of macrolide-antibiotic resistance mediated by ribosomal protein L22

Influence of induced ciprofloxacin resistance on efflux pump activity of Klebsiella pneumoniae

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