Molecular Characterization of Aminoglycoside-modifying Enzymes (AMEs) in Aminoglycoside-Resistant Staphylococcus aureus: A Cross-sectional Study in Northeastern Iran

Document Type : Original Research

Authors

1 Infectious Diseases Research Center, Golestan University of Medical Sciences, Gorgan, Iran

2 Hiroshima Institute of Life Sciences, 7-21, Nishi Asahi-Machi, Minami-ku, Hiroshima-shi, Hiroshima, 734-0002 Japan

3 Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

4 Department of Bacteriology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

5 Department of Biology, Faculty of Basic Sciences, Imam Hossein Comprehensive University, Tehran, Iran

Abstract
Background & Objective: The resistance genes encoding aminoglycoside-modifying enzymes (AMEs) are now widely prevalent in different populations of Staphylococcus aureus. The study aimed to determine the frequency of AMEs-encoding genes in clinical isolates of S. aureus.
Methods: A total of 105 S. aureus isolates were obtained from the different clinical samples; and then were identified by conventional biochemical tests. The antibiotic resistance patterns of the isolates were characterized by the agar disk diffusion method. The distribution of the AMEs and femA genes was determined by conventional and multiplex PCR.
Results: The aminoglycoside resistance rates of kanamycin, tobramycin, gentamicin, amikacin, and netilmicin were 47.6%, 46.6%, 45.7%, 45.7%, and 26.6%, respectively. 16.1% and 1.9% of isolates were MDR and XDR phenotypes, respectively. 21.9% of S. aureus isolates harbored the femA gene and were determined as methicillin-resistant S. aureus (MRSA) clones. The aac(6')/aph(2'') was the most prevalent (47.8%) AME-encoding gene in aminoglycoside-resistant S. aureus, followed by ant(4')-Ia (30.4%) and aph(3')-IIIa (21.7%).
Conclusion:Our study demonstrated that the coexistence of several AMEs and the spread of the resistance determinants like femA in S. aureus clinical isolates are alarming and may contribute to the broadening of aminoglycoside resistance spectra and limit treatment options for staphylococcal infections.

Keywords

Subjects


  1. Zheng X, Fang R, Wang C, Tian X, Lin J, Zeng W, et al. Resistance profiles and biological characteristics of rifampicin‐resistant Staphylococcus aureus small‐colony variants. Infect Drug Resist. 2021 Apr;14:1527-36. [DOI:10.2147/IDR.S301863] [PMID]
  2. Kaur D, Chate S. Study of antibiotic resistance pattern in methicillin-resistant Staphylococcus aureus with special reference to newer antibiotic. J Glob Infect Dis. 2015;7(2):78. [DOI:10.4103/0974-777X.157245] [PMID]
  3. Guo Y, Song G, Sun M, Wang J, Wang Y. Prevalence and therapies of antibiotic-resistance in Staphylococcus aureus. Front Cell Infect Microbiol. 2020 Mar 17;10:107. [DOI:10.3389/fcimb.2020.00107] [PMID]
  4. Lade H, Kim J-S. Bacterial targets of antibiotics in methicillin-resistant Staphylococcus aureus. Antibiotics. 2021 Apr 7;10(4):398. [DOI:10.3390/antibiotics10040398] [PMID
  5. Serio AW, Keepers T, Andrews L, Krause KM. Aminoglycoside revival: review of a historically important class of antimicrobials undergoing rejuvenation. In: Bush K, editor. EcoSal Plus. 2018 Feb 8;8(1). [DOI:10.1128/ecosalplus.esp-0002-2018] [PMID]
  6. Leggett JE. Aminoglycosides. In: Infectious Diseases. Elsevier; 2017. p. 1233-1238.e1. [DOI:10.1016/B978-0-7020-6285-8.00143-X]
  7. Sultan I, Rahman S, Jan AT, Siddiqui MT, Mondal AH, Haq QMR. Antibiotics, resistome and resistance mechanisms: a bacterial perspective. Front Microbiol. 2018 Sep 21;9:2066. [DOI:10.3389/fmicb.2018.02066] [PMID]
  8. Garneau-Tsodikova S, Labby KJ. Mechanisms of resistance to aminoglycoside antibiotics: overview and perspectives. Med Chem Commun. 2016;7(1):11-27. [DOI:10.1039/C5MD00344J] [PMID]
  9. Ramirez MS, Tolmasky ME. Aminoglycoside modifying enzymes. Drug Resist Updat. 2010 Dec;13(6):151-71. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1368764610000385 [DOI:10.1016/j.drup.2010.08.003] [PMID
  10. Peterson E, Kaur P. Antibiotic resistance mechanisms in bacteria: relationships between resistance determinants of antibiotic producers, environmental bacteria, and clinical pathogens. Front Microbiol. 2018 Nov 30;9:2928. [DOI:10.3389/fmicb.2018.02928] [PMID]
  11. Khosravi AD, Jenabi A, Montazeri EA. Distribution of genes encoding resistance to aminoglycoside modifying enzymes in methicillin-resistant Staphylococcus aureus (MRSA) strains. Kaohsiung J Med Sci. 2017 Dec;33(12):587-93. [DOI:10.1016/j.kjms.2017.08.001] [PMID]
  12. Zhang X, Zhou Q, Tang M, Pu J, Zhang J, Lu J, et al. Aminoglycoside resistance and possible mechanisms in Campylobacter spp. isolated from chicken and swine in Jiangsu, China. Front Microbiol. 2021 Oct 8;12:716185. [DOI:10.3389/fmicb.2021.716185] [PMID]
  13. Chen Y-H, Lin S-Y, Lin Y-T, Tseng S-P, Chang C-C, Yu S-Y, et al. Emergence of aac(6′)-Ie-aph(2″)-Ia-positive enterococci with non-high-level gentamicin resistance mediated by IS1216V: adaptation to decreased aminoglycoside usage in Taiwan. J Antimicrob Chemother. 2021 Jun 18;76(7):1689-97. [DOI:10.1093/jac/dkab071] [PMID]
  14. Ziasistani M, Shakibaie MR, Kalantar-Neyestanaki D. Genetic characterization of two vancomycin-resistant Staphylococcus aureus isolates in Kerman, Iran. Infect Drug Resist. 2019 Jul;12:1869-75. [DOI:10.2147/IDR.S205596] [PMID
  15. Choi SM, Kim SH, Kim HJ, Lee DG, Choi JH, Yoo JH, et al. Multiplex PCR for the detection of genes encoding aminoglycoside modifying enzymes and methicillin resistance among Staphylococcus species. J Korean Med Sci. 2003;18(5):631. [DOI:10.3346/jkms.2003.18.5.631] [PMID
  16. Schmitz F-J. The prevalence of aminoglycoside resistance and corresponding resistance genes in clinical isolates of staphylococci from 19 European hospitals. J Antimicrob Chemother. 1999 Feb 1;43(2):253-9. [DOI:10.1093/jac/43.2.253] [PMID]
  17. Mehrotra M, Wang G, Johnson WM. Multiplex PCR for detection of genes for Staphylococcus aureus enterotoxins, exfoliative toxins, toxic shock syndrome toxin 1, and methicillin resistance. J Clin Microbiol. 2000 Mar;38(3):1032-5. [DOI:10.1128/JCM.38.3.1032-1035.2000] [PMID]
  18. Serio AW, Keepers T, Andrews L, Krause KM. Aminoglycoside revival: review of a historically important class of antimicrobials undergoing rejuvenation. In: Bush K, editor. EcoSal Plus. 2018 Feb 8;8(1). [DOI:10.1128/ecosalplus.esp-0002-2018] [PMID]
  19. Ramirez MS, Tolmasky ME. Aminoglycoside modifying enzymes. Drug Resist Updat. 2010;13(6): 151-71. [DOI:10.1016/j.drup.2010.08.003] [PMID]
  20. Beigverdi R, Sattari-Maraji A, Jabalameli F, Emaneini M. Prevalence of genes encoding aminoglycoside-modifying enzymes in clinical isolates of Gram-positive cocci in Iran: a systematic review and meta-analysis. Microb Drug Resist. 2020 Feb 1;26(2):126-35. [DOI:10.1089/mdr.2019.0139] [PMID]
  21. Ardic N, Sareyyupoglu B, Ozyurt M, Haznedaroglu T, Ilga U. Investigation of aminoglycoside modifying enzyme genes in methicillin-resistant staphylococci. Microbiol Res. 2006 Jan;161(1):49-54. [DOI:10.1016/j.micres.2005.05.002] [PMID]
  22. Shokravi Z, Mehrad L, Ramazani A. Detecting the frequency of aminoglycoside modifying enzyme encoding genes among clinical isolates of methicillin-resistant Staphylococcus aureus. BioImpacts. 2017 Aug 23;5(2):87-91. [DOI:10.15171/bi.2015.15] [PMID]
  23. López Díaz MC, Ríos E, Rodríguez-Avial I, Simaluiza RJ, Picazo JJ, Culebras E. In vitro activity of several antimicrobial agents against methicillin-resistant Staphylococcus aureus (MRSA) isolates expressing aminoglycoside-modifying enzymes: potency of plazomicin alone and in combination with other agents. Int J Antimicrob Agents. 2017 Aug;50(2):191-6. [DOI:10.1016/j.ijantimicag.2017.01.039] [PMID]
  24. Seyedi-Marghaki F, Kalantar-Neyestanaki D, Saffari F, Hosseini-Nave H, Moradi M. Distribution of aminoglycoside-modifying enzymes and molecular analysis of the coagulase gene in clinical isolates of methicillin-resistant and methicillin-susceptible Staphylococcus aureus. Microb Drug Resist. 2019 Jan;25(1):47-53. [DOI:10.1089/mdr.2017.0121] [PMID]
  25. Krause KM, Serio AW, Kane TR, Connolly LE. Aminoglycosides: an overview. Cold Spring Harb Perspect Med. 2016 Jun 1;6(6):a027029. [DOI:10.1101/cshperspect.a027029] [PMID
  26. Zhu X, Li P, Qian C, Liu H, Lin H, Zhang X, et al. Prevalence of aminoglycoside resistance genes and molecular characterization of a novel gene, aac(3)-IIg, among clinical isolates of the Enterobacter cloacae complex from a Chinese teaching hospital. Antimicrob Agents Chemother. 2020 Aug 20;64(9):e00852-20. [DOI:10.1128/AAC.00852-20] [PMID]
  27. Baines SL, Jensen SO, Firth N, Gonçalves da Silva A, Seemann T, Carter GP, et al. Remodeling of pSK1 family plasmids and enhanced chlorhexidine tolerance in a dominant hospital lineage of methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2019 May;63(5). [DOI:10.1128/AAC.02356-18] [PMID]
  28. Vannuffel P, Heusterspreute M, Bouyer M, Vandercam B, Philippe M, Gala J-L. Molecular characterization of from and and -based discrimination of staphylococcal species. Res Microbiol. 1999 Mar;150(2):129-41. [DOI:10.1016/S0923-2508(99)80030-8] [PMID]
  29. Benson TE, Prince DB, Mutchler VT, Curry KA, Ho AM, Sarver RW, et al. X-ray crystal structure of Staphylococcus aureus FemA. Structure. 2002 Aug;10(8):1107-15. [DOI:10.1016/S0969-2126(02)00807-9] [PMID]
  30. Mitevska E, Wong B, Surewaard BGJ, Jenne CN. The prevalence, risk, and management of methicillin-resistant Staphylococcus aureus infection in diverse populations across Canada: a systematic review. Pathogens. 2021 Mar 25;10(4):393. [DOI:10.3390/pathogens10040393] [PMID
  31. Dilnessa T, Bitew A. Prevalence and antimicrobial susceptibility pattern of methicillin-resistant Staphylococcus aureus isolated from clinical samples at Yekatit 12 Hospital Medical College, Addis Ababa, Ethiopia. BMC Infect Dis. 2016 Dec 9;16(1):398. [DOI:10.1186/s12879-016-1742-5] [PMID]
  32. Turner NA, Sharma-Kuinkel BK, Maskarinec SA, Eichenberger EM, Shah PP, Carugati M, et al. Methicillin-resistant Staphylococcus aureus: an overview of basic and clinical research. Nat Rev Microbiol. 2019 Apr 8;17(4):203-18. [DOI:10.1038/s41579-018-0147-4] [PMID
  33. Dulon M, Haamann F, Peters C, Schablon A, Nienhaus A. MRSA prevalence in European healthcare settings: a review. BMC Infect Dis. 2011 Dec 20;11(1):138. [DOI:10.1186/1471-2334-11-138] [PMID]
  34. Emaneini M, Taherikalani M, Eslampour M-A, Sedaghat H, Aligholi M, Jabalameli F, et al. Phenotypic and genotypic evaluation of aminoglycoside resistance in clinical isolates of staphylococci in Tehran, Iran. Microb Drug Resist. 2009 Jun;15(2):129-32. [DOI:10.1089/mdr.2009.0869] [PMID]
  35. Khoramrooz SS, Dolatabad SA, Dolatabad FM, Marashifard M, Mirzaii M, Dabiri H, et al. Detection of tetracycline resistance genes, aminoglycoside modifying enzymes, and coagulase gene typing of clinical isolates of Staphylococcus aureus in the southwest of Iran. Iran J Basic Med Sci. 2017 Aug;20(8):912-9.
  36. Giormezis N, Doudoulakakis A, Tsilipounidaki K, Militsopoulou M, Kalogeras G, Stamouli V, et al. Emergence of a mupirocin-resistant, methicillin-susceptible Staphylococcus aureus clone associated with skin and soft tissue infections in Greece. BMC Microbiol. 2021 Dec 3;21(1):203. [DOI:10.1186/s12866-021-02272-5] [PMID]
Volume 20, Issue 1
Winter 2025
Pages 118-125

  • Receive Date 16 August 2024
  • Revise Date 28 September 2024
  • Accept Date 09 November 2024