Genomics epidemiology analysis reveals hidden signatures of drug resistance in Mycobacterium tuberculosis

Mycobacterium tuberculosis (Mtb) causes the majority of reported cases of human tuberculosis (TB), one of the deadliest infectious diseases worldwide. New diagnostic tools and approaches to detect drug-resistance must be introduced by 2025 to achieve the End-TB Strategy goals set for 2030 by the WHO. Genomic epidemiology of TB has allowed the expansion of catalogs listing genetic signatures of Mtb drug-resistance. However, very few Mtb strains from Latin America have participate in previous genomic epidemiologic efforts. Here we present the first functional genomic epidemiology study of drug-resistant Mtb strains in Mexico, incorporating the genomic characterization of 133 genomes, including 53 newly sequenced isolates, to provide a comprehensive phylogeographic analysis of drug resistant Mtb in Mexico. The study evidences the prevalence of Euro-American Lineage L4 (96.2%), featuring a uniform distribution of the sublineages X-type (33.08%), LAM (22.56%), and Haarlem (21.05%). Our results demonstrate low levels of agreement with traditional drug sensitivity tests (DST), raising concerns for drug-resistant isolates lacking any previously reported genetic signatures of resistance. Finally, we propose a novel functional networking tool (FuN-TB) to explore metabolic and cellular signatures of drug resistance. Applying functional genomics approaches to Latin American Mtb genomes will provide new drug-resistance screening targets that can contribute to bed side decision-making and advise local public policy. Abstract importanceWe presented the first phylogeographic analysis of Mycobacterium tuberculosis (Mtb) of Mexico. Our analysis integrates 133 genome sequences and is focused on the identification of genetic signatures associated to drug-resistance. The results show the geographic distribution of sublineages and drug-resistance phenotypic classes. Additionally, we propose a novel functional networking tool (FuN-TB) to explore metabolic and cellular signatures of drug resistance associated. We show for the first time that Mtb isolates from Mexico encode for region-specific genetic signarures of antimicrobial resistance. Applying functional genomics approaches to Latin American Mtb genomes will provide new drug-resistance screening targets that can contribute to bed side decision-making and advise local public policy.