Molecular Characterization Of MDR3 And MDR4 Genes Of Aspergillus Fumigates Isolated From Lung Disease Patients

  • Yass K. Abbass University of Thi-Qar,College of Medicine,Iraq
  • Amal J. Kadhim University of Thi-Qar,College of Medicine,Iraq
  • Khwam R. Hussein University of Thi-Qar,College of Medicine,Iraq
Keywords: Aspergillusfumigatus, MDR genes, azole resistance

Abstract

Background:Triazoles are the mainstay of treatment for aspergillosis. However, azole resistance is an emerging problem reported worldwide in Aspergillus infection mainly caused by A.fumigatus. Increase azole resistance in A.fumigatus has reported with treatment failure and become a significant challenge in effective management of aspergillosis. Aim: The aim of this study is to investigate the triazole-resistant of A. fumigatus and underlying MDR pump genes in viable clinical isolates which obtained from patients suffering pulmonary infections in Thi-Qar province. Methods:The conventional Polymerase Chain Reaction (PCR) was used to confirm antifungal resistance by detecting the presence of MDR pump genes (MDR3 and MDR4). Results:The results of using this technique showed that  A. fumigatusisolates were positive to MDR pump genes with 90% and 96% for MDR3 and MDR4 genes, respectively. Conclusions: Our study revealed that the MDR pump genes are predominant in azole resistance isolates. Furthermore, PCR was proven to be highly effective method for identifying these genes.

References

Adeniyi, B. A., Odelola, H. A., Oso, B.A. (1996) ̒Antimicrobial potentials of Diospyrosmespiliformis(Ebenaceae)̓ , African J Med Medic Sci.,25(3), pp.221–224.

Van Der Linden JWM, Camps SMT, Kampinga GA, Arends JPA, Debets-Ossenkopp YJ, Haas PJA, et al. Aspergillosis due to voriconazole highly resistant Aspergillus fumigatus and recovery of genetically related resistant isolates from domiciles. Clin Infect Dis. 2013;57(4):513–20.

White PL, Posso RB, Barnes RA. Analytical and clinical evaluation of the pathonostics aspergenius assay for detection of invasive aspergillosis and resistance to azole antifungal drugs directly from plasma samples. J Clin Microbiol. 2017;55(8):2356–66.

Vermeulen E, Lagrou K, Verweij PE. Azole resistance in Aspergillus fumigatus: A growing public health concern. Curr Opin Infect Dis. 2013;26(6):493–500.

Chowdhary A, Sharma C, van den Boom M, Yntema JB, Hagen F, Verweij PE, et al. Multi-azole-resistant Aspergillus fumigatus in the environment in Tanzania. J Antimicrob Chemother. 2014;69(11):2979–83.

Wiederhold NP, Gil G, Gutierrez F, Lindner JR, Albataineh MT, Mccarthy DI, et al. Mutations in Aspergillus fumigatus Isolates in the United States. J Clin Microbiol. 2016;54(1):168–71.

Snelders E, Van Der Lee HAL, Kuijpers J, Rijs AJMM, Varga J, Samson RA, et al. Emergence of azole resistance in Aspergillus fumigatus and spread of a single resistance mechanism. PLoS Med. 2008;5(11):1629–37.

van der Linden JWM, Arendrup MC, Warris A, Lagrou K, Pelloux H, Hauser PM, et al. Prospective multicenter international surveillance of azole resistance in Aspergillus fumigatus. Emerg Infect Dis. 2015;21(6):1041–4.

Chowdhary A, Sharma C, Hagen F, Meis JF. Exploring azole antifungal drug resistance in Aspergillus fumigatus with special reference to resistance mechanisms. Futur Microbiol. 2014;9(5):697–711.

Camps SMT, Van Der Linden JWM, Li Y, Kuijper EJ, Van Dissel JT, Verweij PE, et al. Rapid induction of multiple resistance mechanisms in Aspergillus fumigatus during azole therapy: A case study and review of the literature. Antimicrob Agents Chemother. 2012;56(1):10–6.

Cannon RD, Lamping E, Holmes AR, Niimi K, Baret P V., Keniya M V., et al. Efflux-mediated antifungal drug resistance. Clin Microbiol Rev. 2009;22(2):291–321.

Chamilos G, Kontoyiannis DP. Update on antifungal drug resistance mechanisms of Aspergillus fumigatus. Drug Resist Updat. 2005;8(6):344–58.

Nascimento AM, Goldman GH, Park S, Marras SAE, Delmas G, Oza U, et al. Multiple Resistance Mechanisms among. 2003;47(5):1719–26.

Mortensen KL, Mellado E, Lass-Flörl C, Rodriguez-Tudela JL, Johansen HK, Arendrup MC. Environmental study of azole-resistant Aspergillus fumigatus and other aspergilli in Austria, Denmark, and Spain. Antimicrob Agents Chemother. 2010;54(11):4545–9.

Montesinos I, Dodemont M, Lagrou K, Jacobs F, Etienne I, Denis O. New case of azole-resistant Aspergillus fumigatus due to TR46/Y121F/T289A mutation in Belgium. J Antimicrob Chemother. 2014;69(12):3439–40.

Gomez-Lopez A, Forastiero A, Cendejas-Bueno E, Gregson L, Mellado E, Howard SJ, et al. An invertebrate model to evaluate virulence in Aspergillus fumigatus: The role of azole resistance. Med Mycol. 2014;52(3):311–9.

van Paassen J, Russcher A, in ’t Veld - van Wingerden AW, Verweij PE, Kuijper EJ. Emerging aspergillosis by azole-resistant Aspergillus fumigatus at an intensive care unit in the Netherlands, 2010 to 2013. Eurosurveillance [Internet]. 2016;21(30):30300. Available from: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=22541

Hollomon DW, Brent KJ. Combating plant diseases - The Darwin connection. Pest Manag Sci. 2009;65(11):1156–63.

Dunne K, Hagen F, Pomeroy N, Meis JF, Rogers TR. Intercountry Transfer of Triazole-Resistant Aspergillus fumigatus on Plant Bulbs. Clin Infect Dis. 2017;65(1):147–9.

Alvarez-Moreno C, Lavergne RA, Hagen F, Morio F, Meis JF, Le Pape P. Azole-resistant Aspergillus fumigatus harboring TR 34 /L98H, TR 46 /Y121F/T289A and TR 53 mutations related to flower fields in Colombia. Sci Rep [Internet]. 2017;7(August 2016):1–8. Available from: http://dx.doi.org/10.1038/srep45631

Chowdhary A, Kathuria S, Xu J, Meis JF. Emergence of Azole-Resistant Aspergillus fumigatus Strains due to Agricultural Azole Use Creates an Increasing Threat to Human Health. PLoS Pathog. 2013;9(10):3–8.

Slaven JW, Anderson MJ, Sanglard D, Dixon GK, Bille J, Roberts IS, et al. Increased expression of a novel Aspergillus fumigatus ABC transporter gene, atrF, in the presence of itraconazole in an itraconazole resistant clinical isolate. Fungal Genet Biol. 2002;36(3):199–206.

Verweij PE, Snelders E, Kema GH, Mellado E, Melchers WJ. Azole resistance in Aspergillus fumigatus: a side-effect of environmental fungicide use? Lancet Infect Dis [Internet]. 2009;9(12):789–95. Available from: http://dx.doi.org/10.1016/S1473-3099(09)70265-8

Snelders E, Camps SMT, Karawajczyk A, Schaftenaar G, Kema GHJ, van der Lee HA, et al. Triazole fungicides can induce cross-resistance to medical triazoles in Aspergillus fumigatus. PLoS One. 2012;7(3).

Manavathu EK, Abraham OC, Chandrasekar PH. Isolation and in vitro susceptibility to amphoterecin B, itraconazole and posaconazole of voriconazole-resistant laboratory isolates of Aspergillus fumigatus. Clin Microbiol Infect. 2001;7(3):130–7.

Rajendran R, Mowat E, McCulloch E, Lappin DF, Jones B, Lang S, et al. Azole resistance of Aspergillus fumigatus biofilms is partly associated with efflux pump activity. Antimicrob Agents Chemother. 2011;55(5):2092–7.

Capellaro L, Marques R, Perlin D, Park S, Anderson JB, Colombo AL, et al. In Vitro Evolution of Itraconazole Resistance in Aspergillus fumigatus Involves Multiple Mechanisms of Resistance. Antimicrob Agents Chemother. 2004;48(11):4405–13.

Rajendran R, Mowat E, Jones B, Williams C, Ramage G. Prior in vitro exposure to voriconazole confers resistance to amphotericin B in Aspergillus fumigatus biofilms. Int J Antimicrob Agents [Internet]. 2015;46(3):342–5. Available from: http://dx.doi.org/10.1016/j.ijantimicag.2015.03.006

Published
2019-08-02
Section
Articles