Contribution of Efflux to the Emergence of Isoniazid and Multidrug Resistance in Mycobacterium tuberculosis
نویسندگان
چکیده
Multidrug resistant (MDR) tuberculosis is caused by Mycobacterium tuberculosis resistant to isoniazid and rifampicin, the two most effective drugs used in tuberculosis therapy. Here, we investigated the mechanism by which resistance towards isoniazid develops and how overexpression of efflux pumps favors accumulation of mutations in isoniazid targets, thus establishing a MDR phenotype. The study was based on the in vitro induction of an isoniazid resistant phenotype by prolonged serial exposure of M. tuberculosis strains to the critical concentration of isoniazid employed for determination of drug susceptibility testing in clinical isolates. Results show that susceptible and rifampicin monoresistant strains exposed to this concentration become resistant to isoniazid after three weeks; and that resistance observed for the majority of these strains could be reduced by means of efflux pumps inhibitors. RT-qPCR assessment of efflux pump genes expression showed overexpression of all tested genes. Enhanced real-time efflux of ethidium bromide, a common efflux pump substrate, was also observed, showing a clear relation between overexpression of the genes and increased efflux pump function. Further exposure to isoniazid resulted in the selection and stabilization of spontaneous mutations and deletions in the katG gene along with sustained increased efflux activity. Together, results demonstrate the relevance of efflux pumps as one of the factors of isoniazid resistance in M. tuberculosis. These results support the hypothesis that activity of efflux pumps allows the maintenance of an isoniazid resistant population in a sub-optimally treated patient from which isoniazid genetically resistant mutants emerge. Therefore, the use of inhibitors of efflux should be considered in the development of new therapeutic strategies for preventing the emergence of MDR-TB during treatment.
منابع مشابه
Minor Contribution of inhA-15 Mutations to the Rapid Detection of Isoniazid Resistance in Mycobacterium Tuberculosis Isolates
متن کامل
Prevalence ofMultidrug Resistant Mycobacterium tuberculosis by Mycobacteria growth indicator tube in Golestan province, North of Iran
Abstract Background and objectives: Identification and monitoring of multidrug-resistant Mycobacterium tuberculosis strains (MDR) is highlighted by the high risk of their spreading in different areas. Prevalence of these strains was evaluated in Golestan province in northeast of Iran. Material and Methods: Drug susceptibility testing to Isoniazid and rifampin was carried out for 148 clinical sa...
متن کاملA STUDY OF MYCOBACTERIUM TUBERCULOSIS DRUG RESISTANCE IN PULMONARY TUBERCULOSIS
Tuberculosis remains a major public health problem in both developing and developed countries. Drug-resistant tuberculosis is an increasing health problem and serious challenge to tuberculosis (TB) control programs. Information about the susceptibility pattern of Mycobacterium tuberculosis isolates against anti-tuberculosis drugs is an important aspect to TB control. The objectives of the s...
متن کاملDesign, Synthesis, and Evaluation of Novel Hybrid Efflux Pump Inhibitors for Use against Mycobacterium tuberculosis.
Efflux pumps are considered a major potential contributor to the development of various forms of resistance in Mycobacterium tuberculosis leading to the emergence of multidrug-resistant tuberculosis (TB). Verapamil (VER) and tricyclic chemosensitizers such as the phenothiazines are known to possess efflux pump inhibition properties and have demonstrated significant efficacy in various TB diseas...
متن کاملAnti-Mycobacterium Tuberculosis Effects of Folk Medicinal Plants in Iran: A Mini-Systematic Review
The emergence of drug resistance in Mycobacterium tuberculosis is a major challenge in tuberculosis treatment and control. In addition, multidrug resistance (MDR) and, more broadly, extensive drug resistance (XDR) have hampered treatment with common antibiotics. Thus, an herbal medicine containing antimicrobial capability can be a good alternative to antituberculosis drugs. In this study, we re...
متن کامل