scholarly journals In-silico interaction studies on the efflux pumps suggest polymyxins to be better substrate for RND efflux pumps in multi-drug resistant strains of Acinetobacter baumannii

2017 ◽  
Author(s):  
Privita Verma ◽  
Vishvanath Tiwari
Keyword(s):  
Free Energy ◽  
Multidrug Resistance ◽  
In Silico ◽  
Efflux Pump ◽  
Binding Free Energy ◽  
Efflux Pumps ◽  
Drug Resistant ◽  
Rnd Efflux Pumps ◽  
Resistant Strains ◽  
Drug Resistant Strains

Bacterial efflux pumps have emerged as antibiotic resistance determinants and confers multidrug resistance to a broad range of antimicrobials as well as non-antibiotic substances by potentially extruding them out. These are also associated with the virulence and biofilm formation. Thus, development of inhibitors against these effective antibacterial targets can be a highly beneficial approach in order to reverse the multidrug resistance (MDR) in the clinical relevant strains. A keen study on the efflux of foregoing or commonly used antibiotics will contribute in finding substrates that could bind efficiently with these efflux pumps. In the present study, we have explored efflux pumps belonging to Resistance-Nodulation-Division (RND) family as they are found prevalent in gram negative pathogens such as A. baumannii. The two RND efflux pumps under consideration are AdeABC and AcrAB-TolC. For comparative analysis, a non-RND family efflux pump i.e. NorM is selected here. We employed a series of computational techniques ranging from molecular docking to binding free energy estimation and molecular dynamics simulations to determine the binding affinity for different classess of drugs namely aminoglycosides, polymyxins, β-lactams, tetracyclines, glycylcyclines, quinolones and metronidazole against the efflux pumps under study. Our results revealed that class polymyxins has the highest binding affinity with the RND efflux pumps i.e. AcrAB-TolC and AdeABC as well as non-RND efflux pump (NorM). The experimental data was found to much extent in accordance with the binding free energy scores obtained from our in silico analysis. To recapitulate the outcome, polymyxins can possibly be the most efficient substrate for both RND and non-RND efflux pumps, thus, can be used as a reference drug for designing potent efflux pump inhibitors against multi-drug resistant strains.

scholarly journals In-silico interaction studies on the efflux pumps suggest polymyxins to be better substrate for RND efflux pumps in multi-drug resistant strains of Acinetobacter baumannii

2017 ◽  
Author(s):  
Privita Verma ◽  
Vishvanath Tiwari
Keyword(s):  
Free Energy ◽  
Multidrug Resistance ◽  
In Silico ◽  
Efflux Pump ◽  
Binding Free Energy ◽  
Efflux Pumps ◽  
Drug Resistant ◽  
Rnd Efflux Pumps ◽  
Resistant Strains ◽  
Drug Resistant Strains

Bacterial efflux pumps have emerged as antibiotic resistance determinants and confers multidrug resistance to a broad range of antimicrobials as well as non-antibiotic substances by potentially extruding them out. These are also associated with the virulence and biofilm formation. Thus, development of inhibitors against these effective antibacterial targets can be a highly beneficial approach in order to reverse the multidrug resistance (MDR) in the clinical relevant strains. A keen study on the efflux of foregoing or commonly used antibiotics will contribute in finding substrates that could bind efficiently with these efflux pumps. In the present study, we have explored efflux pumps belonging to Resistance-Nodulation-Division (RND) family as they are found prevalent in gram negative pathogens such as A. baumannii. The two RND efflux pumps under consideration are AdeABC and AcrAB-TolC. For comparative analysis, a non-RND family efflux pump i.e. NorM is selected here. We employed a series of computational techniques ranging from molecular docking to binding free energy estimation and molecular dynamics simulations to determine the binding affinity for different classess of drugs namely aminoglycosides, polymyxins, β-lactams, tetracyclines, glycylcyclines, quinolones and metronidazole against the efflux pumps under study. Our results revealed that class polymyxins has the highest binding affinity with the RND efflux pumps i.e. AcrAB-TolC and AdeABC as well as non-RND efflux pump (NorM). The experimental data was found to much extent in accordance with the binding free energy scores obtained from our in silico analysis. To recapitulate the outcome, polymyxins can possibly be the most efficient substrate for both RND and non-RND efflux pumps, thus, can be used as a reference drug for designing potent efflux pump inhibitors against multi-drug resistant strains.

Evaluation of efflux pump gene expression among drug susceptible and drug resistant strains of Mycobacterium tuberculosis from Iran

2015 ◽  
Vol 36 ◽  
pp. 23-26 ◽  
Author(s):  
Jalil Kardan Yamchi ◽  
Mehri Haeili ◽  
Seifu Gizaw Feyisa ◽  
Hossein Kazemian ◽  
Abdolrazagh Hashemi Shahraki ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mycobacterium Tuberculosis ◽  
Efflux Pump ◽  
Drug Resistant ◽  
Resistant Strains ◽  
Drug Resistant Strains

Identification of benzochromene derivatives as a highly specific NorA efflux pump inhibitor to mitigate the drug resistant strains of S. aureus

RSC Advances ◽  
2016 ◽  
Vol 6 (36) ◽  
pp. 30258-30267 ◽  
Author(s):  
Asaithampi Ganesan ◽  
Lowrence Rene Christena ◽  
Himesh Makala Venkata Subbarao ◽  
Ulaganathan Venkatasubramanian ◽  
Raman Thiagarajan ◽  
...  
Keyword(s):  
Efflux Pump ◽  
Drug Resistant ◽  
Efflux Pump Inhibitor ◽  
Resistant Strains ◽  
Drug Resistant Strains

Benzochromene (BC) derivatives identified as potent EPI against NorA efflux pump. BC displays 32-fold ciprofloxacin MIC reversal against NorA overexpressing mutant. BC as an adjuvant with antibiotic can curtail MDRS. aureus.

scholarly journals Characteristics and diversity of mutations in regulatory genes of resistance-nodulation-cell division efflux pumps in association with drug-resistant clinical isolates of Acinetobacter baumannii

2020 ◽  
Author(s):  
Bahare Salehi ◽  
Zohreh Ghalavand ◽  
Abbas Yadegar ◽  
Gita Eslami
Keyword(s):  
Cell Division ◽  
Acinetobacter Baumannii ◽  
Efflux Pump ◽  
Efflux Pumps ◽  
Regulatory Genes ◽  
Clinical Isolates ◽  
Drug Resistant ◽  
Broth Microdilution Method ◽  
Rnd Efflux Pumps ◽  
Multiple Antibiotics

Abstract Background: This study aimed to characterize the regulation and expression of three putative resistance-nodulation-cell division (RND)-type efflux systems and their contribution to multidrug efflux in clinical isolates of Acinetobacter baumannii. Methods: Antimicrobial susceptibility testing (AST) of 95 A. baumannii isolates was determined by Kirby-Bauer disk diffusion for 18 antibiotics and minimum inhibitory concentration (MIC) of colistin was determined by broth microdilution method. Moreover, MIC of five classes of antibiotics was assessed using E-test strips in the presence and absence of phenylalanine-arginine beta-naphthylamide (PAβN). Regulatory genes of RND efflux pumps (AdeRS, AdeL, AdeN and BaeSR) were subjected to sequencing. The relative expression of adeB. adeG and adeJ genes was determined by quantitative real-time PCR (RT-PCR).Results: Overall, majority of isolates (93%) were extensively drug-resistant (XDR). In the phenotypic assay, efflux pump activity was observed in 40% of isolates against multiple antibiotics mainly tigecycline, but not to imipenem. Several amino acid substitutions were detected in the regulatory genes; except in AdeN. Of note, G186V in AdeS were found to be associated with overexpression of their relative efflux pumps. No insertion sequences (ISs) were detected. Conclusions: Our findings outline the role of RND efflux pumps in resistance of A. baumannii against multiple antibiotics particularly tigecycline, and point out importance of a variety of single mutations in the corresponding regulatory systems. Even though it has been concluded that multidrug resistance occurs as a result of a complex sets of different resistant mechanisms.

scholarly journals Characteristics and diversity of mutations in regulatory genes of resistance-nodulation-cell division efflux pumps in association with drug-resistant clinical isolates of Acinetobacter baumannii

2020 ◽  
Author(s):  
Bahare Salehi ◽  
Zohreh Ghalavand ◽  
Abbas Yadegar ◽  
Gita Eslami
Keyword(s):  
Cell Division ◽  
Acinetobacter Baumannii ◽  
Efflux Pump ◽  
Efflux Pumps ◽  
Regulatory Genes ◽  
Clinical Isolates ◽  
Drug Resistant ◽  
Broth Microdilution Method ◽  
Rnd Efflux Pumps ◽  
Multiple Antibiotics

Abstract Background: This study aimed to characterize the regulation and expression of three putative resistance-nodulation-cell division (RND)-type efflux systems and their contribution to multidrug efflux in clinical isolates of Acinetobacter baumannii.Methods: Antimicrobial susceptibility testing (AST) of 95 A. baumannii isolates was determined by Kirby-Bauer disk diffusion for 18 antibiotics and minimum inhibitory concentration (MIC) of colistin was determined by broth microdilution method. Moreover, MIC of five classes of antibiotics was assessed using E-test strips in the presence and absence of phenylalanine-arginine beta-naphthylamide (PAβN). Regulatory genes of RND efflux pumps (AdeRS, AdeL, AdeN and BaeSR) were subjected to sequencing. The relative expression of adeB. adeG and adeJ genes was determined by quantitative real-time PCR (RT-PCR).Results: Overall, majority of isolates (93%) were extensively drug-resistant (XDR). In the phenotypic assay, efflux pump activity was observed in 40% of isolates against multiple antibiotics mainly tigecycline, but not to imipenem. Several amino acid substitutions were detected in the regulatory genes; except in AdeN. Of note, G186V in AdeS were found to be associated with overexpression of their relative efflux pumps. No insertion sequences (ISs) were detected.Conclusions: Our findings outline the role of RND efflux pumps in resistance of A. baumannii against multiple antibiotics particularly tigecycline, and point out importance of a variety of single mutations in the corresponding regulatory systems. Even though it has been concluded that multidrug resistance occurs as a result of a complex sets of different resistant mechanisms.

scholarly journals Characteristics and diversity of mutations in regulatory genes of resistance-nodulation-cell division efflux pumps in association with drug-resistant clinical isolates of Acinetobacter baumannii

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Bahare Salehi ◽  
Zohreh Ghalavand ◽  
Abbas Yadegar ◽  
Gita Eslami
Keyword(s):  
Cell Division ◽  
Acinetobacter Baumannii ◽  
Efflux Pump ◽  
Efflux Pumps ◽  
Regulatory Genes ◽  
Clinical Isolates ◽  
Drug Resistant ◽  
Rnd Efflux Pumps ◽  
Multiple Antibiotics

Abstract Background This study was aimed to characterize the genetic diversity and expression of three putative resistance-nodulation-cell division (RND)-type efflux systems and their contribution to multidrug efflux in clinical isolates of Acinetobacter baumannii. Methods Antimicrobial susceptibility testing of 95 A. baumannii isolates was determined by Kirby-Bauer disk diffusion for 18 antibiotics and minimum inhibitory concentration (MIC) of colistin was determined by the broth microdilution method. Moreover, the MIC of five classes of antibiotics was assessed using E-test strips in the presence and absence of phenylalanine-arginine beta-naphthylamide (PAβN). Regulatory genes of the RND efflux pumps (adeRS, adeL, adeN and baeSR) were subjected to sequencing. The relative expression of adeB, adeG and adeJ genes was determined by quantitative real-time PCR (qRT-PCR). Results Overall, the majority of isolates (94%) were extensively drug-resistant (XDR). In the phenotypic assay, efflux pump activity was observed in 40% of the isolates against multiple antibiotics mainly tigecycline. However, we found no efflux activity against imipenem. Several amino acid substitutions were detected in the products of regulatory genes; except in AdeN. Of note, G186V mutation in AdeS was found to be associated with overexpression of its efflux pump. No insertion sequences were detected. Conclusions Our findings outlined the role of RND efflux pumps in resistance of A. baumannii to multiple antibiotics particularly tigecycline, and pointed out the importance of a variety of single mutations in the corresponding regulatory systems. Further studies are required to decipher the precise role of RND efflux pumps in multidrug-resistant clinical isolates of A. baumannii.

Insights into drug resistance mechanisms in Clostridium difficile

2017 ◽  
Vol 61 (1) ◽  
pp. 81-88 ◽  
Author(s):  
Phurt Harnvoravongchai ◽  
Methinee Pipatthana ◽  
Surang Chankhamhaengdecha ◽  
Tavan Janvilisri
Keyword(s):  
Drug Resistance ◽  
Antibiotic Resistance ◽  
Clostridium Difficile ◽  
Bacterial Infection ◽  
Efflux Pump ◽  
Primary Treatment ◽  
Resistance Mechanisms ◽  
Drug Resistant ◽  
Resistant Strains ◽  
Drug Resistant Strains

The incidence of Clostridium difficile infection has been elevated and becoming common in hospitals worldwide. Although antibiotics usually serve as the primary treatment for bacterial infection including C. difficile infection, limitations and failures have been evident due to drug resistance. Antibiotic resistance in C. difficile has been recognized as one of the most important factors to promote the infection and increase the level of severity and the recurrence rate. Several outbreaks in many countries have been linked to the emergence of hypervirulent drug-resistant strains. This pathogen harbours various mechanisms against the actions of antibiotics. The present study highlights three main drug-resistant strategies in C. difficile including drug inactivation, target modification and efflux pump. Other mechanisms that potentially contribute to drug-resistant traits in this organism are also discussed.

scholarly journals Characteristics and Diversity of Mutations in Regulatory Genes of Resistance-nodulation-cell Division Efflux Pumps in Association With Drug-resistant Clinical Isolates of Acinetobacter Baumannii

2021 ◽  
Author(s):  
Bahare Salehi ◽  
Zohreh Ghalavand ◽  
Abbas Yadegar ◽  
Gita Eslami
Keyword(s):  
Cell Division ◽  
Acinetobacter Baumannii ◽  
Efflux Pump ◽  
Efflux Pumps ◽  
Regulatory Genes ◽  
Clinical Isolates ◽  
Drug Resistant ◽  
Rnd Efflux Pumps ◽  
Multiple Antibiotics

Abstract Background: This study was aimed to characterize the genetic diversity and expression of three putative resistance-nodulation-cell division (RND)-type efflux systems and their contribution to multidrug efflux in clinical isolates of Acinetobacter baumannii.Methods: Antimicrobial susceptibility testing of 95 A. baumannii isolates was determined by Kirby-Bauer disk diffusion for 18 antibiotics and minimum inhibitory concentration (MIC) of colistin was determined by the broth microdilution method. Moreover, the MIC of five classes of antibiotics was assessed using E-test strips in the presence and absence of phenylalanine-arginine beta-naphthylamide (PAβN). Regulatory genes of the RND efflux pumps (adeRS, adeL, adeN and baeSR) were subjected to sequencing. The relative expression of adeB, adeG and adeJ genes was determined by quantitative real-time PCR (RT-PCR).Results: Overall, the majority of isolates (93%) were extensively drug-resistant (XDR). In the phenotypic assay, efflux pump activity was observed in 40% of the isolates against multiple antibiotics mainly tigecycline. However, we found no efflux activity against imipenem. Several amino acid substitutions were detected in the products of regulatory genes; except in AdeN. Of note, G186V mutation in AdeS was found to be associated with overexpression of its efflux pump. No insertion sequences were detected. Conclusions: Our findings outlined the role of RND efflux pumps in resistance of A. baumannii to multiple antibiotics particularly tigecycline, and pointed out the importance of a variety of single mutations in the corresponding regulatory systems. Further studies are required to decipher the precise role of RND efflux pumps in multidrug-resistant clinical isolates of A. baumannii.

scholarly journals Selected Arylpiperazines Are Capable of Reversing Multidrug Resistance in Escherichia coli Overexpressing RND Efflux Pumps

2005 ◽  
Vol 49 (2) ◽  
pp. 849-852 ◽  
Author(s):  
Jürgen A. Bohnert ◽  
Winfried V. Kern
Keyword(s):  
Escherichia Coli ◽  
Multidrug Resistance ◽  
Ethidium Bromide ◽  
Efflux Pump ◽  
Efflux Pumps ◽  
Deficient Mutant ◽  
Efflux Pump Inhibition ◽  
Mutant Strains ◽  
Rnd Efflux Pumps ◽  
Mdr Reversal

ABSTRACT Several arylpiperazines capable of reversing multidrug resistance (MDR) in Escherichia coli overexpressing acrAB and acrEF but not in pump-deficient mutant strains were identified. 1-(1-Naphthylmethyl)-piperazine, one of the more active compounds, enhanced susceptibility to fluoroquinolones and other agents and increased the intracellular concentration of levofloxacin and ethidium bromide, suggesting efflux pump inhibition as the mechanism of MDR reversal.

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