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

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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 structures of isoniazid and ethionamide.
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ijms-17-01417-f001: The structures of isoniazid and ethionamide.

Mentions: To validate the effectiveness of the screening procedure, we sorted out all of the non-synonymous mutations in the drug targets. Overall, five non-synonymous mutations were found in drug targets; three mutations have experimental or theoretical evidence, and the other two are new discoveries (Table 5). One non-synonymous mutation R463L in the katG target gene associated with INH resistance was screened out in dataset 1 (Table 5). The R463L SNP site of katG was predicted to generate resistance for INH, which had been verified by previous experiments [19]. ETH resistance-associated mutations Y155C and R463L of the katG target gene were sorted from gene pairs of dataset 2, as shown in Table 5. The Y155C mutation was consistent with the results of Zhang et al. [16]. The R463L mutation was consistent with the results of INH resistance-associated mutations in dataset 1. ETH is a structural analog of INH (Figure 1). The structural similarity and the existence of cross-resistant phenotypes have suggested that these two drugs share common molecular targets, i.e., inhA and katG [20]. Therefore, we believe that the R463L mutation would lead to the Mtb resistance to ETH. Two EMB resistance-associated mutations, N399T and G406S, of the embB target gene were selected. The G406S mutation was consistent with the results of Zhang et al. and was verified by previous experiments [21]. Comparison with the results of Zhang et al. indicated that the N399T mutation was a new site identified by our method, possibly because the previous study did not consider the joint mutation of gene pairs, and the new mutation site is worth experimental verification.


Bioinformatics Identification of Drug Resistance-Associated Gene Pairs in Mycobacterium tuberculosis
The structures of isoniazid and ethionamide.
© Copyright Policy
Related In: Results  -  Collection

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

ijms-17-01417-f001: The structures of isoniazid and ethionamide.
Mentions: To validate the effectiveness of the screening procedure, we sorted out all of the non-synonymous mutations in the drug targets. Overall, five non-synonymous mutations were found in drug targets; three mutations have experimental or theoretical evidence, and the other two are new discoveries (Table 5). One non-synonymous mutation R463L in the katG target gene associated with INH resistance was screened out in dataset 1 (Table 5). The R463L SNP site of katG was predicted to generate resistance for INH, which had been verified by previous experiments [19]. ETH resistance-associated mutations Y155C and R463L of the katG target gene were sorted from gene pairs of dataset 2, as shown in Table 5. The Y155C mutation was consistent with the results of Zhang et al. [16]. The R463L mutation was consistent with the results of INH resistance-associated mutations in dataset 1. ETH is a structural analog of INH (Figure 1). The structural similarity and the existence of cross-resistant phenotypes have suggested that these two drugs share common molecular targets, i.e., inhA and katG [20]. Therefore, we believe that the R463L mutation would lead to the Mtb resistance to ETH. Two EMB resistance-associated mutations, N399T and G406S, of the embB target gene were selected. The G406S mutation was consistent with the results of Zhang et al. and was verified by previous experiments [21]. Comparison with the results of Zhang et al. indicated that the N399T mutation was a new site identified by our method, possibly because the previous study did not consider the joint mutation of gene pairs, and the new mutation site is worth experimental verification.

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.