Understanding Rifampicin Resistance in Tuberculosis through a Computational Approach

نویسندگان

  • Satish Kumar
  • Lingaraja Jena
چکیده

The disease tuberculosis, caused by Mycobacterium tuberculosis (MTB), remains a major cause of morbidity and mortality in developing countries. The evolution of drug-resistant tuberculosis causes a foremost threat to global health. Most drug-resistant MTB clinical strains are showing resistance to isoniazid and rifampicin (RIF), the frontline anti-tuberculosis drugs. Mutation in rpoB, the beta subunit of DNA-directed RNA polymerase of MTB, is reported to be a major cause of RIF resistance. Amongst mutations in the well-defined 81-base-pair central region of the rpoB gene, mutation at codon 450 (S450L) and 445 (H445Y) is mainly associated with RIF resistance. In this study, we modeled two resistant mutants of rpoB (S450L and H445Y) using Modeller9v10 and performed a docking analysis with RIF using AutoDock4.2 and compared the docking results of these mutants with the wild-type rpoB. The docking results revealed that RIF more effectively inhibited the wild-type rpoB with low binding energy than rpoB mutants. The rpoB mutants interacted with RIF with positive binding energy, revealing the incapableness of RIF inhibition and thus showing resistance. Subsequently, this was verified by molecular dynamics simulations. This in silico evidence may help us understand RIF resistance in rpoB mutant strains.

برای دانلود رایگان متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Computational Approach in Understanding Mechanism of Action of Isoniazid and Drug Resistance

Most Multi Drug Resistance and Extremely Drug Resistance clinical strains of Mycobacterium tuberculosis are found to be resistant to the anti-tuberculousis drugs such as Isoniazid and Rifampicin. The mechanism of action and drug resistance due to Isoniazid has been the subject of extensive study. According to Tuberculosis drug resistance mutation database, 22 genes/proteins are associated with ...

متن کامل

Mutations in the RpoB Gene of Multidrug-Resistant Mycobacterium Tuberculosis Isolates from Semarang, Indonesia

ABSTRACTTuberculosis is an infectious disease which occurs widely in the world and becomes one of the top 10 causes of death worldwide. Mutations of the RpoB gene cause the resistance of Mycobacterium tuberculosis to rifampicin that contributes to the occurrence of MDR-TB. This study aimed to determine the pattern of rpoB gene polymorphisms in the MDR M. tuberculosis in Semarang, Indonesia. Mos...

متن کامل

Frequency and Molecular Characterization of Rifampicin-Resistance in rpoB Region of Multiple Drug Resistance (MDR) Isolates from Tuberculosis Patients in Southern Endemic Region of Iran

The aim of this study was to investigate the frequency, location and type of rpoB gene mutations in Mycobacterium tuberculosis (MTB) collected from patients in the southern endemic region of Iran. Drug susceptibility testing was determined by using the BACTEC system and the center for diseases control’s (CDC) standard conventional proportional method. In 29 rifampicin-resistant MTB (85%) isolat...

متن کامل

Prevalence of Antibiotic Resistance to Isonicotinylhydrazide and Rifampicin in Culture Positive Pulmonary Tuberculosis Patients from 2014 to 2016 in Zahedan City, Iran

Background: One third of the world’s population is infected with TB, and the disease is known as the second deadly global infection, even more severe than measles. The disease kills about 2 million people a year. Approximately 8 million people in the world are affected by advanced tuberculosis (TB). Objective: The current study aimed to determine the freq...

متن کامل

Systematic Review of the Performance of Rapid Rifampicin Resistance Testing for Drug-Resistant Tuberculosis

INTRODUCTION Rapid tests for rifampicin resistance may be useful for identifying isolates at high risk of drug resistance, including multidrug-resistant TB (MDR-TB). However, choice of diagnostic test and prevalence of rifampicin resistance may both impact a diagnostic strategy for identifying drug resistant-TB. We performed a systematic review to evaluate the performance of WHO-endorsed rapid ...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

عنوان ژورنال:

دوره 12  شماره 

صفحات  -

تاریخ انتشار 2014