Role of the cell envelope stress regulators BaeR and CpxR in control of RND-type multidrug efflux pumps and transcriptional cross talk with exopolysaccharide synthesis in Erwinia amylovora
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Infections caused by multidrug resistance (MDR) of Gram-negative bacteria have become one of the most severe public health problems worldwide. The main mechanism that confers MDR to bacteria is drug efflux pumps, as they expel a wide range of compounds, especially antibiotics. Among the different types of drug efflux pumps, the resistance nodulation division (RND) superfamily confers MDR to various Gram-negative bacteria species. The AcrAB-TolC multidrug efflux pump, from E. coli, a member of RND, is the best-characterized example and an excellent model for understanding MDR because of an abundance of functional and structural data. Small molecule inhibitors that target the AcrAB-TolC drug efflux pump represent a new solution to reversing MDR in Gram-negative bacteria and restoring the efficacy of various used drugs that are clinically relevant to these pathogens, especially in the high shortage of drugs for multidrug-resistant Gram-negative bacteria. This review will investigate solutions of MDR in Gram-negative bacteria by studying the inhibition of the AcrAB-TolC multidrug efflux pump.
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The number of multidrug-resistant bacteria is rapidly spreading worldwide. Among the various mechanisms determining resistance to antimicrobial agents, multidrug efflux pumps play a noteworthy role because they export extraneous and noxious substrates from the inside to the outside environment of the bacterial cell contributing to multidrug resistance (MDR) and, consequently, to the failure of anti-infective therapies. The expression of multidrug efflux pumps can be under the control of transcriptional regulators and two-component systems (TCS). TCS are a major mechanism by which microorganisms sense and reply to external and/or intramembrane stimuli by coordinating the expression of genes involved not only in pathogenic pathways but also in antibiotic resistance. In this review, we describe the influence of TCS on multidrug efflux pump expression and activity in some Gram-negative and Gram-positive bacteria. Taking into account the strict correlation between TCS and multidrug efflux pumps, the development of drugs targeting TCS, alone or together with already discovered efflux pump inhibitors, may represent a beneficial strategy to contribute to the fight against growing antibiotic resistance.
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The emergence of multidrug-resistant Klebsiella pneumoniae is a worldwide problem. K. pneumoniae possesses numerous resistant genes in its genome. We isolated mutants resistant to various antimicrobials in vitro and investigated the importance of intrinsic genes in acquired resistance. The isolation frequency of the mutants was 10-7-10-9. Of the multidrug-resistant mutants, hyper-multidrug-resistant mutants (EB256-1, EB256-2, Nov1-8, Nov2-2, and OX128) were identified, and accelerated efflux activity of ethidium from the inside to the outside of the cells was observed in these mutants. Therefore, we hypothesized that the multidrug efflux pump, especially RND-type efflux pump, would be related to changes of the phenotype. We cloned all RND-type multidrug efflux pumps from the K. pneumoniae genome and characterized them. KexEF and KexC were powerful multidrug efflux pumps, in addition to AcrAB, KexD, OqxAB, and EefABC, which were reported previously. It was revealed that the expression of eefA was increased in EB256-1 and EB256-2: the expression of oqxA was increased in OX128; the expression of kexF was increased in Nov2-2. It was found that a region of 1,485 bp upstream of kexF, was deleted in the genome of Nov2-2. K. pneumoniae possesses more potent RND-multidrug efflux systems than E. coli. However, we revealed that most of them did not contribute to the drug resistance of our strain at basic levels of expression. On the other hand, it was also noted that the overexpression of these pumps could lead to multidrug resistance based on exposure to antimicrobial chemicals. We conclude that these pumps may have a role to maintain the intrinsic resistance of K. pneumoniae when they are overexpressed. The antimicrobial chemicals selected many resistant mutants at the same minimum inhibitory concentration (MIC) or a concentration slightly higher than the MIC. These results support the importance of using antibiotics at appropriate concentrations at clinical sites.
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OBJECTIVE To investigate the distribution of 11 efflux pump genes in multidrug-resistant Escherichia coli.METHODS PCR was used to detect the 11 efflux pump genes(emrB,emrD,emrE,mdfA,sugE,mdtI,tehA,oqxA,qacE△1,qacE,smr-2),and database retrieval of these genes were carried out in BIOCYC.RESULTS Nine efflux pump genes,including emrB,emrD,emrE,mdfA,sugE,mdtI,tehA,oqxA and qacE△1,were detected in 20 strains of multidrug-resistant Escherichia coli,the detection rates being 100.0%,100.0%,95.0%,100.0%,100.0%,100.0%,75.0%,100.0% and 20.0%,respectively;but qacE and smr-2 were not detected.A total of 6 to 9 genes were detected in each single isolate.CONCLUSION The carrier rate of efflux pump genes in multidrug-resistant E.coli is high,which may play an important role in inducing multiple drug resistance.
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Multidrug efflux pump is the main reason for bacterial multidrug resistance, and it’s a chal- lenge for the treatment of infectious diseases. Analysis of multidrug efflux pump offers us the mecha- nism and treatment ideas of bacterial multidrug resistance. New advances have been made in the study of Escherichia coli AcrAB-TolC efflux pump structure and its regulation, which provides data for the multidrug resistance research in pathogenic bacterium. Progress in this area is reviewed here.
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Genotypic characterization, based on the analysis of restriction fragment length polymorphism of the recA gene fragment PCR product ( recA PCR-RFLP), was performed on members of the former Erwinia genus. PCR primers deduced from published recA gene sequences of Erwinia carotovora allowed the amplification of an approximately 730 bp DNA fragment from each of the 19 Erwinia species tested. Amplified recA fragments were compared using RFLP analysis with four endonucleases ( Alu I, Hin fI, Tas I and Tru 1I), allowing the detection of characteristic patterns of RFLP products for most of the Erwinia species. Between one and three specific RFLP groups were identified among most of the species tested ( Erwinia amylovora , Erwinia ananas , Erwinia cacticida , Erwinia cypripedii , Erwinia herbicola , Erwinia mallotivora , Erwinia milletiae , Erwinia nigrifluens , Erwinia persicina , Erwinia psidii , Erwinia quercina , Erwinia rhapontici , Erwinia rubrifaciens , Erwinia salicis , Erwinia stewartii , Erwinia tracheiphila , Erwinia uredovora , Erwinia carotovora subsp. atroseptica , Erwinia carotovora subsp. betavasculorum , Erwinia carotovora subsp. odorifera and Erwinia carotovora subsp. wasabiae ). However, in two cases, Erwinia chrysanthemi and Erwinia carotovora subsp. carotovora , 15 and 18 specific RFLP groups were detected, respectively. The variability of genetic patterns within these bacteria could be explained in terms of their geographic origin and/or wide host-range. The results indicated that PCR-RFLP analysis of the recA gene fragment is a useful tool for identification of species and subspecies belonging to the former Erwinia genus, as well as for differentiation of strains within E. carotovora subsp. carotovora and E. chrysanthemi.
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Abstract The appearance of resistant strains of Gram-negative bacteria against antibiotics has compromised the efficiency of treatment. Multidrug resistance (MDR) is mainly due to the involvement of Resistance-nodulation division (RND) efflux pumps that actively pump out the drugs. For inhibition of the pump, it is essential to understand the structure as well as molecular basis of the process. Molecular dynamics (MD)simulationis employed to understand the conformational dynamics and functional mechanism of the pumps. Keywords: Molecular dynamics (MD) simulations, Resistance-nodulation division (RND) efflux pumps, multidrug resistance (MDR) Cite this Article Puzari M, Chetia P. Molecular Dynamics Simulation of RND Efflux Pumps Involved in Multidrug Resistance. Research & Reviews: A Journal of Bioinformatics. 2016; 3(2): 20–24p.
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API 20E and API 50CHE systems (72 phenotypic tests) were applied to a total of 529 strains, including 421 strains belonging to 21 different Erwinia species, 66 Enterobacter agglomerans strains, 18 Escherichia adecarboxylata strains, and 24 strains of 16 other enterobacteria. The results were analyzed numerically by using the Gower similarity coefficient and the unweighted average linkage method. The named Erwinia strains were distributed over 27 phena, some of which also contained strains received as Enterobacter agglomerans. Strains of Erwinia amylovora, Erwinia chrysanthemi, Erwinia cypripedii, Erwinia mallotivora, Erwinia nigrifluens, Erwinia paradisiaca, Erwinia quercina, Erwinia rubrifaciens, Erwinia salicis, Erwinia stewartii, and Escherichia adecarboxylata constitute separate phena. Erwinia carotovora, Erwinia chrysanthemi, and Erwinia rhapontici are heterogeneous, but distinct from each other and from the other phena. The type strains of Erwinia herbicola, Enterobacter agglomerans, and Erwinia milletiae fall into one phenon, and strains of Erwinia ananas and Erwinia uredovora are in a single phenon. Obviously misnamed Erwinia herbicola and Enterobacter agglomerans strains can be assigned to other species, such as Erwinia cypripedii, Erwinia ananas, Erwinia rhapontici, Rahnella aquatilis, Enterobacter sakazakii, Escherichia adecarboxylata, and Serratia marcescens or to as-yet-unnamed phena. Three Erwinia carnegieana strains, but not the type strain, form one phenon. Erwinia dissolvens and Erwinia nimipressuralis should be allocated to Enterobacter. Our results confirm the heterogeneous taxonomic structure of the genus Erwinia.
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Multidrug efflux pumps are inner membrane transporters that export multiple antibiotics from the inside to the outside of bacterial cells, contributing to bacterial multidrug resistance (MDR). Postgenomic analysis has demonstrated that numerous multidrug efflux pumps exist in bacteria. Also, the co-crystal structural analysis of multidrug efflux pumps revealed the drug recognition and export mechanisms, and the inhibitory mechanisms of the pumps. A single multidrug efflux pump can export multiple antibiotics; hence, developing efflux pump inhibitors is crucial in overcoming infectious diseases caused by multidrug-resistant bacteria. This review article describes the role of multidrug efflux pumps in MDR, and their physiological functions and inhibitory mechanisms.
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