Differential Expression of Resistant and Efflux Pump Genes in MDR-TB Isolates

2020 ◽  
Vol 20 (2) ◽  
pp. 271-287 ◽  
Author(s):  
Manaf AlMatar ◽  
Işıl Var ◽  
Begüm Kayar ◽  
Fatih Köksal
Keyword(s):  
Drug Resistance ◽  
Target Genes ◽  
Efflux Pump ◽  
Gene Mutations ◽  
Clinical Isolates ◽  
Pomegranate Juice ◽  
Drug Efflux ◽  
Mdr Tb ◽  
Drug Efflux Pump

Background: Numerous investigations demonstrate efflux as a worldwide bacterial mode of action which contributes to the resistance of drugs. The activity of antibiotics, which subjects to efflux, can be improved by the combined usage of efflux inhibitors. However, the efflux role to the overall levels of antibiotic resistance of clinical M. tuberculosis isolates is inadequately comprehended and is still disregarded by many. Method: Here, we assessed the contribution of resistant genes associated with isoniazid (INH) and rifampin (R) resistance to the levels of drug resistance in the (27) clinical isolates of MDR-TB. Additionally, the role of the resistance for six putative drug efflux pump genes to the antibiotics was investigated. The level of katG expression was down-regulated in 24/27 (88.88%) of MDR-TB isolates. Of the 27 MDR-TB isolates, inhA, oxyR-ahpC, and rpoB showed either overexpression or up-regulation in 8 (29.62%), 4 (14.81 %), and 24 (88.88%), respectively. Moreover, the efflux pump genes drrA, drrB, efpA, Rv2459, Rv1634, and Rv1250 were overexpressed under INH/RIF plus fresh pomegranate juice (FPJ) stress signifying the efflux pumps contribution to the overall levels of the resistance of MDR-TB isolates. Conclusion: These results displayed that the levels of drug resistance of MDR-TB clinical isolates are due to combination among drug efflux pump and the presence of mutations in target genes, a truth which is often ignored by the specialists of tuberculosis in favour of the almost undoubted significance of drug target- gene mutations for the resistance in M. tuberculosis.

scholarly journals The synergistic role of ATP-dependent drug efflux pump and focal adhesion signaling pathways in vinorelbine resistance in lung cancer

2018 ◽  
Vol 7 (2) ◽  
pp. 408-419 ◽  
Author(s):  
Takao Nakanishi ◽  
Toshi Menju ◽  
Shigeto Nishikawa ◽  
Koji Takahashi ◽  
Ryo Miyata ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Signaling Pathways ◽  
Focal Adhesion ◽  
Efflux Pump ◽  
Drug Efflux ◽  
Drug Efflux Pump

scholarly journals Role of Active Efflux in Association with Target Gene Mutations in Fluoroquinolone Resistance in Clinical Isolates of Vibrio cholerae

2002 ◽  
Vol 46 (8) ◽  
pp. 2676-2678 ◽  
Author(s):  
Somesh Baranwal ◽  
Keya Dey ◽  
T. Ramamurthy ◽  
G. Balakrish Nair ◽  
Manikuntala Kundu
Keyword(s):  
Vibrio Cholerae ◽  
Target Gene ◽  
Target Genes ◽  
Gene Mutations ◽  
Proton Motive Force ◽  
Quinolone Resistance ◽  
Clinical Isolates ◽  
Fluoroquinolone Resistance ◽  
Active Efflux

ABSTRACT Quinolones are among the drugs of choice in the management of cholera caused by Vibrio cholerae. In this study, we demonstrate that, in addition to mutations detected in the target genes gyrA and parC, proton motive force-dependent efflux is involved in quinolone resistance in clinical isolates of V. cholerae.

scholarly journals Identification of residues in ABCG2 affecting protein trafficking and drug transport, using co-evolutionary analysis of ABCG sequences

2015 ◽  
Vol 35 (4) ◽  
Author(s):  
Ameena J. Haider ◽  
Megan H. Cox ◽  
Natalie Jones ◽  
Alice J. Goode ◽  
Katherine S. Bridge ◽  
...  
Keyword(s):  
Amino Acids ◽  
Drug Resistance ◽  
Protein Trafficking ◽  
Drug Transport ◽  
Protein Targeting ◽  
Efflux Pump ◽  
Efflux Pumps ◽  
Drug Efflux ◽  
Evolutionary Analysis ◽  
Drug Efflux Pump

Determining how efflux pumps function is important to understanding their role in drug resistance. We have identified amino acids in a human drug efflux pump that affect interaction with substrate and protein targeting.

scholarly journals Mutations in efflux pump Rv1258c (Tap) cause resistance to pyrazinamide and other drugs inM. tuberculosis

2018 ◽  
Author(s):  
Jiayun Liu ◽  
Wanliang Shi ◽  
Shuo Zhang ◽  
Gail Cassell ◽  
Dmitry A. Maslov ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Drug Targets ◽  
Drug Exposure ◽  
Efflux Pump ◽  
Active Form ◽  
Point Mutations ◽  
Drug Susceptibility ◽  
Clinical Isolates

AbstractAlthough drug resistance inM. tuberculosisis mainly caused by mutations in drug activating enzymes or drug targets, there is increasing interest in possible role of efflux in causing drug resistance. Previously, efflux genes are shown upregulated upon drug exposure or implicated in drug resistance in overexpression studies, but the role of mutations in efflux pumps identified in clinical isolates in causing drug resistance is unknown. Here we investigated the role of mutations in efflux pump Rv1258c (Tap) from clinical isolates in causing drug resistance inM. tuberculosisby constructing point mutations V219A, S292L in Rv1258c in the chromosome ofM. tuberculosisand assessed drug susceptibility of the constructed mutants. Interestingly, V219A, S292L point mutations caused clinically relevant drug resistance to pyrazinamide (PZA), isoniazid (INH), and streptomycin (SM), but not to other drugs inM. tuberculosis. While V219A point mutation conferred a low level resistance, the S292L mutation caused a higher level of resistance. Efflux inhibitor piperine inhibited INH and PZA resistance in the S292L mutant but not in the V219A mutant. S292L mutant had higher efflux activity for pyrazinoic acid (the active form of PZA) than the parent strain. We conclude that point mutations in the efflux pump Rv1258c in clinical isolates can confer clinically relevant drug resistance including PZA and could explain some previously unaccounted drug resistance in clinical strains. Future studies need to take efflux mutations into consideration for improved detection of drug resistance inM. tuberculosisand address their role in affecting treatment outcome in vivo.

scholarly journals Evaluation the Expression of Efflux Pump Genes “Tap & P55 in Mycobacterium Tuberculosis Clinical Isolates in Fars, Iran

2020 ◽  
Author(s):  
Fardis Khoob ◽  
Milad Shahini Shams Abadi ◽  
Nahal Hadi ◽  
Farzaneh Avazzadeh ◽  
Zahra Zarei
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Target Genes ◽  
Efflux Pump ◽  
Expression Level ◽  
Genetic Mutations ◽  
Antimicrobial Sensitivity ◽  
Probable Role ◽  
Tuberculosis Therapy

Abstract BackgroundThe increasing drug resistance in Mycobacterium tuberculosis isolates has become a global problem for tuberculosis therapy programs. Genetic mutations in rifampin (RIF), one of the key drugs in the treatment of tuberculosis are main mechanism of resistant to this drug in M. tuberculosis. Absence of mutation in target genes, other mechanisms such as efflux pump suggests possible role of drug resistant.The objective of this study was to find out mutations in rpoB genes in rifampin resistant isolates and to compare the expression level of tap and p55 efflux pump genes in non mutated isolates, mutated isolates in rpoB genes and susceptible isolates.MethodsIn this study, antimicrobial sensitivity test on first line drugs was performed on 200 M. tuberculosis isolates, obtained from TB center in Shiraz (IRAN) and genetic mutations were evaluated in rpoB gene in RIF resistant isolates by multiplex PCR, followed expression level evaluated by Real-time PCR.Resultsout of the 200 isolates tested, 23 (34.33%) showed resistant to RIF. 12 of 23 RIF resistant isolates have mutation in rpoB gene, and frequency of mutations in codons 516, 526 and 531 were 3 (25%), 4 (33.33%) and 5 (41.67%) respectively. The expression level of tap and p55 genes was considerably higher in resistant isolates which had no mutation compared to the expression level of genes in the isolates which had mutation in target genes.ConclusionThe accumulating data suggest the probable role of efflux pump in M. tuberculosis drug resistance, the validation of data needs further phenotypic assays of these pumps.

scholarly journals C. albicans Zn Cluster Transcription Factors Tac1 and Znc1 are Activated by Farnesol to Up Regulate a Transcriptional Program Including the Multi-Drug Efflux Pump CDR1

2018 ◽  
Author(s):  
Zhongle Liu ◽  
John M. Rossi ◽  
Lawrence C. Myers
Keyword(s):  
Transcription Factors ◽  
Quorum Sensing ◽  
Biofilm Formation ◽  
Target Genes ◽  
Efflux Pump ◽  
Close Relative ◽  
Drug Efflux ◽  
Dna Binding Specificity ◽  
Drug Efflux Pump ◽  
Hyphal Formation

AbstractFarnesol, a quorum-sensing molecule, inhibits C. albicans hyphal formation, affects its biofilm formation and dispersal, and impacts its stress response. Several aspects of farnesol’s mechanism of action remain incompletely uncharacterized. Among these are a thorough accounting of the cellular receptors and transporters for farnesol. This work suggests these themes are linked through the Zn cluster transcription factors Tac1 and Znc1, and their induction of the multi-drug efflux pump Cdr1. Specifically, we have demonstrated that Tac1 and Znc1 are functionally activated by farnesol through a mechanism that mimics other means of hyperactivation of Zn cluster transcription factors. This is consistent with our observation that many genes acutely induced by farnesol are dependent on TAC1, ZNC1, or both. A related molecule, 1-dodecanol, invokes a similar TAC1/ZNC1 response, while several other proposed C. albicans quorum sensing molecules do not. TAC1 and ZNC1 both bind to and up-regulate the CDR1 promoter in response to farnesol. Differences in inducer and DNA binding specificity lead to Tac1 and Znc1 having overlapping, but non-identical, regulons. TAC1 and ZNC1 dependent farnesol induction of their target genes was inversely related to the level of CDR1 present in the cell, suggesting a model in which induction of CDR1 by Tac1 and Znc1 leads to an increase in farnesol efflux. Consistent with this premise, our results show that CDR1 expression, and its regulation by TAC1 and ZNC1, facilitates growth in the presence of high farnesol concentrations in C. albicans, and certain strains of its close relative C. dubliniensis.

scholarly journals Role of AbeS, a Novel Efflux Pump of the SMR Family of Transporters, in Resistance to Antimicrobial Agents in Acinetobacter baumannii

2009 ◽  
Vol 53 (12) ◽  
pp. 5312-5316 ◽  
Author(s):  
Vijaya Bharathi Srinivasan ◽  
Govindan Rajamohan ◽  
Wondwossen A. Gebreyes
Keyword(s):  
Escherichia Coli ◽  
Acinetobacter Baumannii ◽  
Antimicrobial Agents ◽  
Efflux Pump ◽  
Multidrug Resistant ◽  
Drug Efflux ◽  
Drug Efflux Pump ◽  
Resistance Expression ◽  
Multidrug Resistant Strain

ABSTRACT In this study, a chromosomally encoded putative drug efflux pump of the SMR family, named AbeS, from a multidrug-resistant strain of Acinetobacter baumannii was characterized to elucidate its role in antimicrobial resistance. Expression of the cloned abeS gene in hypersensitive Escherichia coli host KAM32 resulted in decreased susceptibility to various classes of antimicrobial agents, detergents, and dyes. Deletion of the abeS gene in A. baumannii confirmed its role in conferring resistance to these compounds.

scholarly journals Screening antibiotics using an Hoechst 33342 dye-accumulation assay to detect efflux activity in Acinetobacter baumannii clinical isolates

2018 ◽  
Vol 11 (4) ◽  
pp. 371-378 ◽  
Author(s):  
In-Sun Choi ◽  
Choon-Mee Kim ◽  
Sook-Jin Jang
Keyword(s):  
Multidrug Resistance ◽  
Acinetobacter Baumannii ◽  
Efflux Pump ◽  
Multidrug Resistant ◽  
Clinical Isolates ◽  
Drug Efflux ◽  
Hoechst 33342 ◽  
Efflux Pump Inhibitor ◽  
Significant Difference

AbstractBackgroundUnderstanding the contribution of efflux pumps to the resistance of antibiotics is useful when considering strategies for antimicrobial therapy.ObjectivesTo assess the role of efflux activity on the resistance of antibiotics commonly used in hospitals.MethodsWe analyzed the efflux activity of 120 clinical isolates of Acinetobacter baumannii using an Hoechst 33342 (H33342) dye-accumulation assay. We compared the indicators for efflux activity of susceptible and non-susceptible groups of each of 16 tested antibiotics. To determine the role of efflux activity on resistance to an antibiotic, we used 3 criteria based on the results of the H33342-accumulation assay.ResultsThe evaluation suggests that efflux activity contributed to resistance to the following 11 antibiotics: cefepime, cefotaxime, ceftazidime, ciprofloxacin, gentamicin, imipenem, meropenem, piperacillin, piperacillin/tazobactam, ticarcillin/ clavulanic acid, and tigecycline. However, ampicillin/sulbactam, minocycline, and trimethoprim/sulfamethoxazole did not meet the criteria, suggesting resistance may not be mediated by efflux activity. A significant difference in efflux activity was observed between bacteria belonging to the multidrug-resistant Acinetobacter baumannii (MDRAB) group and those belonging to the non-MDRAB group.ConclusionsEfflux activity may contribute to multidrug resistance and particularly resistance to numerous antibiotics used in hospitals. These antibiotics would be good candidates for combination therapeutic regimens consisting of an antibiotic and an efflux pump inhibitor as an adjuvant to combat drug efflux.

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