Roles of TolC-Dependent Multidrug Transporters of
            <i>Escherichia coli</i>
            in Resistance to β-Lactams

Nishino, Kunihiko; Yamada, Jun; Hirakawa, Hidetada; Hirata, Takahiro; Yamaguchi, Akihito

doi:10.1128/aac.47.9.3030-3033.2003

Cited by 133 publications

(127 citation statements)

References 30 publications

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“…In the case of Escherichia coli, energydependent efflux of bile salts was observed (Thanassi et 1997). Moreover, several multidrug efflux transporters have already been described as having involvement in resistance to deoxycholate and other constituents of bile (Nishino & Yamaguchi, 2001;Nishino et al, 2003;Xu et al, 2003), thus implying that the multidrug efflux transporters themselves play a significant role in resistance to bile, as well as to other antimicrobial agents.…”

Section: Introductionmentioning

confidence: 99%

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VmeAB, an RND-type multidrug efflux transporter in Vibrio parahaemolyticus

et al. 2007

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Genes vmeA and vmeB, encoding a multidrug efflux transporter in the halophilic bacterium Vibrio parahaemolyticus, have been cloned using a drug-hypersusceptible Escherichia coli strain as the host. Cells of E. coli KAM33 (DacrAB DydhE) carrying the vmeAB region from V. parahaemolyticus conferred much higher MICs for a variety of antimicrobial agents than did control cells. Cells possessing VmeAB under energized conditions maintained very low intracellular concentrations of ethidium. This was as expected for an energy-dependent efflux system, and supports the notion -based on sequence homology -that VmeAB belongs to the resistance nodulation cell division (RND) family of multidrug efflux transporters. It is likely that VmeAB forms functional complexes with the outer-membrane protein TolC in E. coli, because introduction of vmeAB into cells of E. coli KAM43, which lacks the tolC gene, failed to elevate the MICs for any of the antimicrobial agents tested. Therefore, a V. parahaemolyticus homologue of tolC was also cloned, designated vpoC, and was introduced together with vmeAB into cells of E. coli KAM43. The MICs of all agents tested were raised and were comparable to the values observed in E. coli KAM33 harbouring a plasmid carrying vmeAB. Finally, a vmeAB-deficient mutant of V. parahaemolyticus was constructed (designated TM3). TM3 showed slightly higher susceptibility than the parental V. parahaemolyticus to some antimicrobial agents. Survival rate of the TM3 when exposed to deoxycholate decreased compared with that of the parent. INTRODUCTIONVibrio parahaemolyticus, a slightly halophilic marine bacterium, is a major cause of food poisoning in Japan (Obata et al., 2001; WHO, 1999;Yamazaki et al., 2003) and many other countries (Cabanillas-Beltran et al., 2006; CDC, 2006;Lozano-Leon et al., 2003;McLaughlin et al., 2005; Sen et al., 2007;Su et al., 2005a). The organism has some peculiar physiological characteristics, such as a very fast growth rate, a Na + requirement for growth (Baumann & Schubert, 1984) and an ability to live in diverse environments including brackish water (Kumazawa & Kato, 1985), on estuarine algae (Kumazawa et al., 1991), and in mammalian hosts, including humans (Yamamoto & Yokota, 1989).In achieving human infection, V. parahaemolyticus survives in the intestine and especially in the duodenum, where bile acids and their conjugates are abundant. Bile acids are anionic detergents and support the digestion of fats in the intestine. In addition, bile has bactericidal effects due to its membrane-solvent property (Provenzano et al., 2000). Thus, bile resistance of enteropathogenic bacteria is thought to be important for their survival in the intestine. Some enteropathogenic bacteria have been shown to possess systems to protect from the actions of bile. In the case of Vibrio cholerae, the outer-membrane component TolC Vc , which had already been identified as a component of some multidrug efflux transporters (sometimes called multidrug efflux pumps), was found to contribute to resistance to bile,...

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Section: Introductionmentioning

confidence: 99%

“…(Nishino & Yamaguchi, 2001;Nishino et al, 2003;Xu et al, 2003), thus implying that the multidrug efflux transporters themselves play a significant role in resistance to bile, as well as to other antimicrobial agents.…”

Section: Introductionmentioning

confidence: 99%

VmeAB, an RND-type multidrug efflux transporter in Vibrio parahaemolyticus

et al. 2007

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“…Earlier, we reported that the MdtEF multi-drug efflux pump requires TolC to function. 12 YdeO-mediated multi-drug resistance was completely suppressed by deleting the tolC or mdtEF gene (Table 3). Although nothing is known of the potential YdeO-binding consensus sequence, it was reported that YdeO has an ability to bind the intergenic region between hdeD and gadE, located upstream of mdtEF.…”

Section: Discussionmentioning

confidence: 99%

“…Deletion of tolC from the DacrB strain increased susceptibility to many antimicrobial agents and chemical compounds, including cloxacillin, nafcillin, erythromycin and SDS (Table 3), which is in good agreement with earlier reports. 12 The tolC deletion completely inhibited YdeOmediated multi-drug resistance (Table 3). This result indicates that YdeO-mediated multi-drug resistance is attributable to increased expression of a TolC-dependent drug efflux pump.…”

Section: Overexpression Of Ydeo Increases Resistance To Oxacillinmentioning

confidence: 98%

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Role of the AraC–XylS family regulator YdeO in multi-drug resistance of Escherichia coli

et al. 2009

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Multi-drug efflux pumps contribute to the resistance of Escherichia coli to many antibiotics and biocides. In this study, we report that the AraC-XylS family regulator YdeO increases the multi-drug resistance of E. coli through activation of the MdtEF efflux pump. Screening of random fragments of genomic DNA for their ability to increase b-lactam resistance led to the isolation of a plasmid containing ydeO, which codes for the regulator of acid resistance. When overexpressed, ydeO significantly increased the resistance of the E. coli strain to oxacillin, cloxacillin, nafcillin, erythromycin, rhodamine 6G and sodium dodecyl sulfate. The increase in drug resistance caused by ydeO overexpression was completely suppressed by deleting the multifunctional outer membrane channel gene tolC. TolC interacts with different drug efflux pumps. Quantitative real-time PCR showed that YdeO activated only mdtEF expression and none of the other drug efflux pumps in E. coli. Deletion of mdtEF completely suppressed the YdeO-mediated multi-drug resistance. YdeO enhances the MdtEF-dependent drug efflux activity in E. coli. Our results indicate that the YdeO regulator, in addition to its role in acid resistance, increases the multi-drug resistance of E. coli by activating the MdtEF multi-drug efflux pump. Keywords: drug efflux pump; Escherichia coli; MdtEF; multidrug resistance; YdeO INTRODUCTION Multi-drug efflux pumps cause serious problems in cancer chemotherapy and in the treatment of bacterial infections. Bacterial drug resistance is often associated with multi-drug efflux pumps that decrease drug accumulation in the cell. 1,2 Bacterial multi-drug efflux pumps are classified into five families on the basis of sequence similarity: major facilitator, resistance-nodulation-cell division (RND), small multi-drug resistance, multidrug and toxic compound extrusion, and ATP-binding cassette. [3][4][5] Of these, RND family efflux pumps play major roles in both intrinsic and elevated resistance of Gram-negative bacteria to a wide range of compounds, including b-lactams. 1,6-12 RND efflux pumps require two other proteins to function: a membrane fusion protein and an outer membrane protein.Many drug efflux pumps in Escherichia coli need TolC to function. [12][13][14][15] TolC is responsible for resistance to various antibiotics, including b-lactams, 12 quinolones 16 and macrolides. 17 Bacterial genome sequencing enables us to trace drug-resistance genes. [18][19][20] There are many putative and proven drug efflux pumps in the E. coli genome, and we have identified earlier 20 functional drug efflux pumps. 9,20 As many such efflux pumps have overlapping substrate spectra, 9 it is intriguing that bacteria, with their economically organized genomes, harbor such large sets of multi-drug efflux genes.

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Role of xenobiotic transporters in bacterial drug resistance and virulence

Nishino

Yamaguchi

2008

IUBMB Life

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SummarySince the discovery of antibiotic therapeutics, the battles between humans and infectious diseases have never been stopped. Humans always face the appearance of a new bacterial drug-resistant strain followed by new antibiotic development. However, as the genome sequences of infectious bacteria have been gradually determined, a completely new approach has opened. This approach can analyze the entire gene resources of bacterial drug resistance. Through analysis, it may be possible to discover the underlying mechanism of drug resistance that will appear in the future. In this review article, we will first introduce the method to analyze all the xenobiotic transporter genes by using the genomic information. Next, we will discuss the regulation of xenobiotic transporter gene expression through the two-component signal transduction system, the principal environmental sensing and response system in bacteria. Furthermore, we will also introduce the virulence roles of xenobiotic transporters, which is an ongoing research area.2008 IUBMB IUBMB Life, 60(9): 569-574, 2008

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Roles of TolC-Dependent Multidrug Transporters of Escherichia coli in Resistance to β-Lactams

Cited by 133 publications

References 30 publications

VmeAB, an RND-type multidrug efflux transporter in Vibrio parahaemolyticus

VmeAB, an RND-type multidrug efflux transporter in Vibrio parahaemolyticus

Role of the AraC–XylS family regulator YdeO in multi-drug resistance of Escherichia coli

Role of xenobiotic transporters in bacterial drug resistance and virulence

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