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Bioinformatics Identification of Drug Resistance-Associated Gene Pairs in Mycobacterium tuberculosis

View Article: PubMed Central - PubMed

ABSTRACT

Tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis (Mtb). Due to the extensive use of anti-tuberculosis drugs and the development of mutations, the emergence and spread of multidrug-resistant tuberculosis is recognized as one of the most dangerous threats to global tuberculosis control. Some single mutations have been identified to be significantly linked with drug resistance. However, the prior research did not take gene-gene interactions into account, and the emergence of transmissible drug resistance is connected with multiple genetic mutations. In this study we use the bioinformatics software GBOOST (The Hong Kong University, Clear Water Bay, Kowloon, Hong Kong, China) to calculate the interactions of Single Nucleotide Polymorphism (SNP) pairs and identify gene pairs associated with drug resistance. A large part of the non-synonymous mutations in the drug target genes that were included in the screened gene pairs were confirmed by previous reports, which lent sound solid credits to the effectiveness of our method. Notably, most of the identified gene pairs containing drug targets also comprise Pro-Pro-Glu (PPE) family proteins, suggesting that PPE family proteins play important roles in the drug resistance of Mtb. Therefore, this study provides deeper insights into the mechanisms underlying anti-tuberculosis drug resistance, and the present method is useful for exploring the drug resistance mechanisms for other microorganisms.

No MeSH data available.


The distance of the active site of the KatG target and Arg463 residue (the distance was approximately 58.172 Å, far from drug binding site).
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ijms-17-01417-f002: The distance of the active site of the KatG target and Arg463 residue (the distance was approximately 58.172 Å, far from drug binding site).

Mentions: Interestingly, according to the research report of Phelan et al., there is a strong association between the (shorter) distance of the mutation to the ligand in the protein structure and INH resistance (greater minimum inhibitory concentrations (MIC) values), and the distance between the mutation location and drug binding site was not greater than 9.93 Å [15]. The R463L mutation was not reported in their results. The crystal structure of the KatG protein has been reported (PDB code: 2CCA) [22], and structural analysis revealed that the mutation of R463L is located far from the drug binding site (the distance was approximately 58.172 Å, much greater than 9.93 Å), as shown in Figure 2. This result also lends credit to the present method, which can identify the resistance mutations that far from the drug binding site.


Bioinformatics Identification of Drug Resistance-Associated Gene Pairs in Mycobacterium tuberculosis
The distance of the active site of the KatG target and Arg463 residue (the distance was approximately 58.172 Å, far from drug binding site).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5037696&req=5

ijms-17-01417-f002: The distance of the active site of the KatG target and Arg463 residue (the distance was approximately 58.172 Å, far from drug binding site).
Mentions: Interestingly, according to the research report of Phelan et al., there is a strong association between the (shorter) distance of the mutation to the ligand in the protein structure and INH resistance (greater minimum inhibitory concentrations (MIC) values), and the distance between the mutation location and drug binding site was not greater than 9.93 Å [15]. The R463L mutation was not reported in their results. The crystal structure of the KatG protein has been reported (PDB code: 2CCA) [22], and structural analysis revealed that the mutation of R463L is located far from the drug binding site (the distance was approximately 58.172 Å, much greater than 9.93 Å), as shown in Figure 2. This result also lends credit to the present method, which can identify the resistance mutations that far from the drug binding site.

View Article: PubMed Central - PubMed

ABSTRACT

Tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis (Mtb). Due to the extensive use of anti-tuberculosis drugs and the development of mutations, the emergence and spread of multidrug-resistant tuberculosis is recognized as one of the most dangerous threats to global tuberculosis control. Some single mutations have been identified to be significantly linked with drug resistance. However, the prior research did not take gene-gene interactions into account, and the emergence of transmissible drug resistance is connected with multiple genetic mutations. In this study we use the bioinformatics software GBOOST (The Hong Kong University, Clear Water Bay, Kowloon, Hong Kong, China) to calculate the interactions of Single Nucleotide Polymorphism (SNP) pairs and identify gene pairs associated with drug resistance. A large part of the non-synonymous mutations in the drug target genes that were included in the screened gene pairs were confirmed by previous reports, which lent sound solid credits to the effectiveness of our method. Notably, most of the identified gene pairs containing drug targets also comprise Pro-Pro-Glu (PPE) family proteins, suggesting that PPE family proteins play important roles in the drug resistance of Mtb. Therefore, this study provides deeper insights into the mechanisms underlying anti-tuberculosis drug resistance, and the present method is useful for exploring the drug resistance mechanisms for other microorganisms.

No MeSH data available.