Simultaneous Detection of Drug-resistant Mutations in Mycobacterium tuberculosis and Determining their Role through In Silico Docking

生物信息学 结核分枝杆菌 抗药性 生物 突变体 多路复用 药品 遗传学 基因 计算生物学 肺结核 医学 药理学 病理
作者
Somanna Ajjamada Nachappa,Sumana M. Neelambike,Ahmad Sarikhani,Nallur B. Ramachandra
出处
期刊:Infectious disorders drug targets [Bentham Science Publishers]
卷期号:21 (1): 134-141 被引量:1
标识
DOI:10.2174/1871526520666200318111140
摘要

: A molecular method for diagnosis of drug-resistant Tuberculosis is Multiplex allele-specific PCR (MAS-PCR), which is more time-efficient. Also, understanding the role of mutations when translated to protein, in causing resistance helps better drug designing. Aims: To study MAS-PCR in the detection of drug resistance in comparison to DNA sequencing, and understand the mechanism of interaction of drugs with mutant proteins in Mycobacterium tuberculosis. Methods: Detection of drug-resistant mutations using MAS-PCR and validation through DNA sequencing. MAS-PCR targeted four genes, iniA for the drug Ethambutol, rpsL and rrs for Streptomycin, and gyrA for Fluoroquinolone resistance, respectively. Further, the sequence data was analysed and modelled to study the effect on interaction of the anti-TB drug molecule with the target protein using in silico docking. Results: We identified drug-resistant mutations in four out of 95 isolates with one of them carrying a mutation at codon iniA501, two at gyrA94, and one for both iniA501 and gyrA94 using MAS-PCR. DNA sequencing confirmed drug-resistant mutations in only two isolates, whereas two others had mutation adjacent to the target allele. Molecular docking showed Estimated Free Energy of Binding (ΔG) being higher for Fluoroquinolone binding with GyrA D94V mutant. Both, wild and mutant IniA interact with EMB but had no significant effect on binding energy. Conclusions: DNA sequencing-based drug resistance detection of TB is more accurate than MAS-PCR. Understanding the role of mutations in influencing the drug-protein interaction will help in designing effective drug alternatives.
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