Genes related to DNA damage repair in Mycobacterium tuberculosis are critical for survival and genomic diversification. The aim of this study is to compare the presence of SNPs in genes related to DNA damage repair in sensitive and drug-resistant M. tuberculosis genomes isolated from patients with and without type 2 diabetes mellitus (T2DM). We collected 399 M. tuberculosis L4 genomes from several public repositories; 224 genomes belonging to hosts without T2DM, of which 123 (54.9%) had drug sensitive tuberculosis (TB) and 101 (45.1%) had drug resistance (DR)-TB; and 175 genomes from individuals with T2DM, of which 100 (57.1%) had drug sensitive TB and 75 (42.9%) had DR-TB. The presence of SNPs in the coding regions of 65 genes related to DNA damage repair was analyzed and compared with the resistance profile and the presence/absence of T2DM in the host. The results show the phylogenetic relationships of some SNPS and L4 sub-lineages, as well as differences in the distribution of SNPs present in DNA damage repair-related genes related to the resistance profile of the infecting strain and the presence of T2DM in the host. Given these differences, it was possible to generate two discriminant functions to distinguish between drug sensitive and drug resistant genomes, as well as patients with or without T2DM.

BackgroundType 2 diabetes mellitus (T2DM) has been associated with treatment failure, and the development of drug resistance in tuberculosis (TB). Also, whole-genome sequencing has provided a better understanding and allowed the growth of knowledge about polymorphisms in genes associated with drug resistance. Considering the above, this study analyzes genome sequences to evaluate the influence of type 2 diabetes mellitus in the development of mutations related to tuberculosis drug resistance. M. tuberculosis isolates from individuals with (n=74), and without (n=74) type 2 diabetes mellitus was recovered from online repositories, and further analyzed. ResultsThe results showed the presence of 591 SNPs with similar proportions between diabetics, and non-diabetics individuals (48.2% vs. 51.7%), but with no significant relationship. A greater number of mutations associated with rifampicin resistance was observed in the T2DM-TB individuals (19.3% vs. 12.5%), and the exclusive presence of rpoBQ432L, rpoBQ432P, rpoBS441L, and rpoBH445L variants. While these variants are not private to T2DM-TB cases they are globally rare highlighting a potential role of T2DM. The phylogenetic analysis showed 12 sublineages, being 4.1.1.3, and 4.1.2.1 the most prevalent in T2DM-TB individuals but not differing from those most prevalent in their geographic location. Four clonal complexes were found, however, no significant relationship with T2DM was observed. Samples size and potential sampling biases prevented us to look for significant associations. ConclusionsThe occurrence of globally rare rifampicin variants identified only in isolates from individuals with T2DM could be due to the hyperglycemic environment within the host. Therefore, further studies about the dynamics of SNPs’ generation associated with antibiotic resistance in patients with diabetes mellitus are necessary.

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Background Type 2 diabetes mellitus (T2DM) has been associated with treatment failure, and the development of drug resistance in tuberculosis (TB). Also, whole-genome sequencing has provided a better understanding and allowed the growth of knowledge about polymorphisms in genes associated with drug resistance. Considering the above, this study analyzes genome sequences to evaluate the influence of type 2 diabetes mellitus in the development of mutations related to tuberculosis drug resistance. M. tuberculosis isolates from individuals with (n = 74), and without (n = 74) type 2 diabetes mellitus was recovered from online repositories, and further analyzed. Results The results showed the presence of 431 SNPs with similar proportions between diabetics, and non-diabetics individuals (48% vs. 52%), but with no significant relationship. A greater number of mutations associated with rifampicin resistance was observed in the T2DM-TB individuals (23.2% vs. 16%), and the exclusive presence of rpoBQ432L, rpoBQ432P, rpoBS441L, and rpoBH445L variants. While these variants are not private to T2DM-TB cases they are globally rare highlighting a potential role of T2DM. The phylogenetic analysis showed 12 sublineages, being 4.1.1.3, and 4.1.2.1 the most prevalent in T2DM-TB individuals but not differing from those most prevalent in their geographic location. Four clonal complexes were found, however, no significant relationship with T2DM was observed. Samples size and potential sampling biases prevented us to look for significant associations. Conclusions The occurrence of globally rare rifampicin variants identified only in isolates from individuals with T2DM could be due to the hyperglycemic environment within the host. Therefore, further studies about the dynamics of SNPs’ generation associated with antibiotic resistance in patients with diabetes mellitus are necessary.