Mutations in sugar metabolism-related genes driving global drug-resistant Mycobacterium tuberculosis transmission revealed by whole-genome sequencing.

BACKGROUND: Tuberculosis (TB) continues to represent a significant global health challenge, particularly due to the emergence of drug-resistant strains that hinder TB control initiatives. Elucidating the mechanisms underlying the proliferation of drug-resistant strains is essential for developing effective strategies to address this public health threat. METHODS: Whole-genome sequencing was conducted on 13,525 Mycobacterium tuberculosis isolates. Genes associated with sugar metabolism were obtained from the National Center for Biotechnology Information (NCBI) Gene database. Analytical approaches, including Random Forests, Gradient Boosting Decision Trees, and Generalized Linear Mixed Models were used to identify mutation sites in sugar metabolism genes that contribute to transmission of Multidrug-Resistant Tuberculosis (MDR-TB). RESULTS: Significant associations were identified between specific gene mutations and transmission clusters in MDR-TB. Notable mutations include Rv0650 (C113T, C316T), sugB C734A, epiA C43T, Rv151c C8G, Rv1520 (C138T, T618C, A649C), Rv2038c G282A, Rv2039c (G391T, T283G), Rv2040c G835C, Rv2316 C161G, and sugI C1268T. Additionally, mutations associated with MDR-TB transmission clusters, include Rv0650 C316T, Rv151c T809C, and Rv2039c C794T. Certain mutations, such as Rv0539 G588T and uspA G379C, were found to increase the risk of cross-regional transmission in MDR clades. The presence of Rv1512 (epiA, C462T) and Rv2038c T161G was associated with an increased therisk of developing MDR isolates compared to single drug resistant (SDR) isolates. CONCLUSION: Mutations in sugar metabolism genes significantly contribute to the global transmission of MDR-TB. Identifing these genetic determinants canguide targeted interventions to control drug-resistant strains and improve TB management. Further research is required to elucidate mechanism underlying mechanisms of transmission and resistance development. CLINICAL TRIAL NUMBER: Not applicable.