Tuberculosis and Respiratory Diseases

The Korean Academy of Tuberculosis and Respiratory Diseases (대한결핵및호흡기학회)
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The Role of N-Acetyl Transferases on Isoniazid Resistance from Mycobacterium tuberculosis and Human: An In Silico Approach

  • Unissa, Ameeruddin Nusrath (Department of Biomedical Informatics, National Institute for Research in Tuberculosis (NIRT), Indian Council of Medical Research (ICMR)) ;
  • Sukumar, Swathi (Department of Biomedical Informatics, National Institute for Research in Tuberculosis (NIRT), Indian Council of Medical Research (ICMR)) ;
  • Hanna, Luke Elizabeth (Department of Biomedical Informatics, National Institute for Research in Tuberculosis (NIRT), Indian Council of Medical Research (ICMR))
  • Received : 2017.03.04
  • Accepted : 2017.05.08
  • Published : 2017.07.31
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Abstract

Background:N-acetyl transferase (NAT) inactivates the pro-drug isoniazid (INH) to N-acetyl INH through a process of acetylation, and confers low-level resistance to INH in Mycobacterium tuberculosis (MTB). Similar to NAT of MTB, NAT2 in humans performs the same function of acetylation. Rapid acetylators, may not respond to INH treatment efficiently, and could be a potential risk factor, for the development of INH resistance in humans. Methods: To understand the contribution of NAT of MTB and NAT2 of humans in developing INH resistance using in silico approaches, in this study, the wild type (WT) and mutant (MT)-NATs of MTB, and humans, were modeled and docked, with substrates and product (acetyl CoA, INH, and acetyl INH). The MT models were built, using templates 4BGF of MTB, and 2PFR of humans. Results: On the basis of docking results of MTB-NAT, it can be suggested that in comparison to the WT, binding affinity of MT-G207R, was found to be lower with acetyl CoA, and higher with acetyl-INH and INH. In case of MT-NAT2 from humans, the pattern of score with respect to acetyl CoA and acetyl-INH, was similar to MT-NAT of MTB, but revealed a decrease in INH score. Conclusion: In MTB, MT-NAT revealed high affinity towards acetyl-INH, which can be interpreted as increased formation of acetyl-INH, and therefore, may lead to INH resistance through inactivation of INH. Similarly, in MT-NAT2 (rapid acetylators), acetylation occurs rapidly, serving as a possible risk factor for developing INH resistance in humans.

Keywords

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