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Vaez H, Vaez V, Khademi F. Effect of Mutation in Efflux Pump Regulatory Protein (MexR) of Pseudomonas aeruginosa: A Bioinformatic Study. mljgoums. 2017; 11 (6) :35-41
URL: http://mlj.goums.ac.ir/article-1-1021-en.html
1- Department of Microbiology, School of Medicine, Zabol University of Medical Sciences, Zabol, Iran
2- Department of Veterinary Medicine, Islamic Azad University, Karaj branch, Karaj, Iran
3- Department of Microbiology, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran , f.khademi@arums.ac.ir
Abstract:   (9931 Views)
           Background and Objectives: Pseudomonas aeruginosa is an important non-fermenting gram-negative hospital-acquired pathogen. Treatment of P. aeruginosa infections has become more challenging due to overexpression of efflux pumps. The aim of the present study was to apply in silico analysis to evaluate the structure of the efflux pump regulatory protein, MexR, and impact of mutation on its stability and function.
         Methods: Different bioinformatics tools including EXPASY, PROTEER, TECCOFFE, iStable, I-Mutant 2, STRING, ESPript, GOR IV, and PDB were used in the study.
          Results: Aliphatic and instability indices were 104.15, and 46.52, respectively, indicating that the protein has a relatively short half-life. Most mutations decreased protein stability. Twenty-four mutations were identified as deleterious, with negative impact on the protein’s function.
         Conclusion: Determination of structure, variability, and function of MexR could be useful for modeling of treatment and control of multidrug resistant P. aeruginosa, with overexpressed efflux pump. We found that MexR is a relatively unstable and conserved protein and the majority of mutations decrease its stability.

         Keywords: Pseudomonas aeruginosa, MexR protein, Drug resistance, drug resistance multiple.

Full-Text [PDF 303 kb]   (1276 Downloads)    
Research Article: Original Paper |
Received: 2017/11/20 | Accepted: 2017/08/29 | Published: 2017/11/20 | ePublished: 2017/11/20

1. Vaez H, Faghri J, Nasr Esfahani B, Moghim S, Fazeli H, Sedighi M, et al. Antibiotic Resistance Patterns and Genetic Diversity in Clinical Isolates of Pseudomonas aeruginosa Isolated From Patients of a Referral Hospital, Isfahan, Iran. Jundishapur J Microbiol. 2015;8(8):e20130. doi: 10.5812/jjm.20130v2. [DOI:10.5812/jjm.20130v2]
2. Lister PD, Wolter DJ, Hanson ND. Antibacterial-resistant Pseudomonas aeruginosa: clinical impact and complex regulation of chromosomally encoded resistance mechanisms. Clin Microbiol Rev. 2009; 22(4): 582-610. doi: 10.1128/CMR.00040-09. [DOI:10.1128/CMR.00040-09]
3. Vaez H, Moghim S, Nasr Esfahani B, Ghasemian Safaei H. Clonal Relatedness among Imipenem-Resistant Pseudomonas aeruginosa Isolated from ICU-Hospitalized Patients. Crit Care Res Pract. 2015; 2015:983207. doi: 10.1155/2015/983207. [DOI:10.1155/2015/983207]
4. Dreier J, Ruggerone P. Interaction of antibacterial compounds with RND e ffl ux pumps in Pseudomonas aeruginosa. Front Microbiol. 2015; 6: 660. doi: 10.3389/fmicb.2015.00660. [DOI:10.3389/fmicb.2015.00660]
5. Sun J, Deng Z, Yan A. Bacterial multidrug efflux pumps: mechanisms, physiology and pharmacological exploitations. Biochem Biophys Res Commun. 2014; 453(2): 254-67. doi: 10.1016/j.bbrc.2014.05.090. [DOI:10.1016/j.bbrc.2014.05.090]
6. Vaez H, Faghri J, Isfahani BN, Moghim S, Yadegari S, Fazeli H, et al. Efflux pump regulatory genes mutations in multidrug resistance Pseudomonas aeruginosa isolated from wound infections in Isfahan hospitals. Adv Biomed Res. 2014;3:117. doi: 10.4103/2277-9175.133183. [DOI:10.4103/2277-9175.133183]
7. Rasamiravaka T, Labtani Q, Duez P, El Jaziri M. The formation of biofilms by Pseudomonas aeruginosa: a review of the natural and synthetic compounds interfering with control mechanisms. Biomed Res Int. 2015; 2015: 759348. doi: 10.1155/2015/759348. [DOI:10.1155/2015/759348]
8. Teng S, Srivastava AK, Wang L. Sequence feature-based prediction of protein stability changes upon amino acid substitutions. BMC Genomics. 2010;11 (Suppl 2): S5. doi: 10.1186/1471-2164-11-S2-S5. [DOI:10.1186/1471-2164-11-S2-S5]
9. Tamura K, Stecher G, Peterson D, Filipski A, Kumar S. MEGA6: Molecular Evolutionary Genetics Analysis version 6.0. Mol Biol Evol. 2013; 30(12): 2725-9. doi: 10.1093/molbev/mst197. [DOI:10.1093/molbev/mst197]
10. Gasteiger E, Hoogland C, Gattiker A, Duvaud S, Wilkins MR, Appel RD. The Proteomics Protocols Handbook. Humana Press. 2005.
11. Robert X, Gouet P. Deciphering key features in protein structures with the new ENDscript server. Nucleic Acids Res. 2014;42(Web Server issue):W320-4. doi: 10.1093/nar/gku316. [DOI:10.1093/nar/gku316]
12. Omasits U, Ahrens CH, Muller S, Wollscheid B. Protter: interactive protein feature visualization and integration with experimental proteomic data. Bioinformatics. 2014; 30(6): 884-6. doi: 10.1093/bioinformatics/btt607. [DOI:10.1093/bioinformatics/btt607]
13. Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, et al. STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 2015; 43(Database issue): D447-52. doi: 10.1093/nar/gku1003. [DOI:10.1093/nar/gku1003]
14. Chen CW, Lin J, Chu YW. iStable: off-the-shelf predictor integration for predicting protein stability changes. BMC Bioinformatics. 2013; 14 Suppl 2: S5. doi: 10.1186/1471-2105-14-S2-S5.
15. Adewoye L, Sutherland A, Srikumar R, Poole K. The mexR repressor of the mexAB-oprM multidrug efflux operon in Pseudomonas aeruginosa: characterization of mutations compromising activity. J Bacteriol. 2002; 184(15):4308-12. doi: 10.1128/JB.184.15.4308-4312.2002. [DOI:10.1128/JB.184.15.4308-4312.2002]
16. Andresen C, Jalal S, Aili D, Wang Y, Islam S, Jarl A, et al. Critical biophysical properties in the Pseudomonas aeruginosa efflux gene regulator MexR are targeted by mutations conferring multidrug resistance. Protein Sci. 2010; 19(4): 680-92. doi: 10.1002/pro.343. [DOI:10.1002/pro.343]
17. Campo Esquisabel AB, Rodriguez MC, Campo-Sosa AO, Rodriguez C, Martinez-Martinez L. Mechanisms of resistance in clinical isolates of Pseudomonas aeruginosa less susceptible to cefepime than to ceftazidime. Clin Microbiol Infect. 2011; 17(12): 1817-22. doi: 10.1111/j.1469-0691.2011.03530.x. [DOI:10.1111/j.1469-0691.2011.03530.x]
18. Higgins PG, Fluit AC, Milatovic D, Verhoef J, Schmitz FJ. Mutations in GyrA, ParC, MexR and NfxB in clinical isolates of Pseudomonas aeruginosa. Int J Antimicrob Agents. 2003; 21(5): 409-13. [DOI:10.1016/S0924-8579(03)00009-8]
19. Hocquet D, Bertrand X, Kohler T, Talon D, Plesiat P. Genetic and phenotypic variations of a resistant Pseudomonas aeruginosa epidemic clone. Antimicrob Agents Chemother. 2003; 47(6): 1887-94. doi: 10.1128/AAC.47.6.1887-1894.2003. [DOI:10.1128/AAC.47.6.1887-1894.2003]
20. Llanes C, Hocquet D, Vogne C, Benali-Baitich D, Neuwirth C, Plesiat P. Clinical strains of Pseudomonas aeruginosa overproducing MexAB-OprM and MexXY efflux pumps simultaneously. Antimicrob Agents Chemother. 2004; 48(5): 1797-802. doi: 10.1128/AAC.48.5.1797-1802.2004. [DOI:10.1128/AAC.48.5.1797-1802.2004]
21. Quale J, Bratu S, Gupta J, Landman D. Interplay of efflux system, ampC, and oprD expression in carbapenem resistance of Pseudomonas aeruginosa clinical isolates. Antimicrob Agents Chemother. 2006; 50(5): 1633-41. [DOI:10.1128/AAC.50.5.1633-1641.2006]
22. Saito K, Akama H, Yoshihara E, Nakae T. Mutations affecting DNA-binding activity of the MexR repressor of mexR-mexA-mexB-oprM operon expression. J Bacteriol. 2003;185(20): 6195-8. doi: 10.1128/JB.185.20.6195-6198.2003. [DOI:10.1128/JB.185.20.6195-6198.2003]
23. Srikumar R, Paul CJ, Poole K. Influence of mutations in the mexR repressor gene on expression of the MexA-MexB-oprM multidrug efflux system of Pseudomonas aeruginosa. J Bacteriol. 2000; 182(5): 1410-4. [DOI:10.1128/JB.182.5.1410-1414.2000]
24. Suman G, Khan M, Sabitha K, Jamil K. Mutation in mexR-gene leading to drug resistance in corneal keratitis in human. Indian J Exp Biol. 2006; 44(11): 929-36. Tomas M, Doumith M, Warner M, Turton JF, Beceiro A, Bou G, et al. Efflux pumps, OprD porin, AmpC beta-lactamase, and multiresistance in Pseudomonas aeruginosa isolates from cystic fibrosis patients. Antimicrob Agents Chemother. 2010; 54(5): 2219-24. doi: 10.1128/AAC.00816-09. [DOI:10.1128/AAC.00816-09]
25. Ziha-Zarifi I, Llanes C, Kohler T, Pechere JC, Plesiat P. In vivo emergence of multidrug-resistant mutants of Pseudomonas aeruginosa overexpressing the active efflux system MexA-MexB-OprM. Antimicrob Agents Chemother. 1999; 43(2): 287-91.
26. Alekshun MN, Levy SB. Molecular mechanisms of antibacterial multidrug resistance. Cell. 2007; 128(6): 1037-50. DOI:10.1016/j.cell.2007.03.004. [DOI:10.1016/j.cell.2007.03.004]
27. Idicula-Thomas S, Balaji PV. Understanding the relationship between the primary structure of proteins and their amyloidogenic propensity: clues from inclusion body formation. Protein Eng Des Sel. 2005; 18(4): 175-80. DOI:10.1093/protein/gzi022. [DOI:10.1093/protein/gzi022]
28. Reva B, Antipin Y, Sander C. Predicting the functional impact of protein mutations: application to cancer genomics. Nucleic Acids Res. 2011; 39(17): e118. doi: 10.1093/nar/gkr407. [DOI:10.1093/nar/gkr407]
29. Gummadi SN. What is the role of thermodynamics on protein stability? . Biotechnology and Bioprocess Engineering. 2003; 8(1): 9-18. [DOI:10.1007/BF02932892]
30. Lim D, Poole K, Strynadka NC. Crystal structure of the MexR repressor of the mexRAB-oprM multidrug efflux operon of Pseudomonas aeruginosa. J Biol Chem. 2002; 277(32): 29253-9. [DOI:10.1074/jbc.M111381200]

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