Abstract:
(1) BACKGROUND : This study was aimed to identify universal genetic markers of multidrug
resistance (MDR) in Mycobacterium tuberculosis (Mtb) and establish statistical associations among
identified mutations to enhance understanding of MDR in Mtb and inform diagnostic and treatment
development. (2) METHODS : GWAS analysis and the statistical evaluation of identified polymorphic
sites within protein-coding genes of Mtb were performed. Statistical associations between specific
mutations and antibiotic resistance were established using attributable risk statistics. (3) RESULTS :
Sixty-four polymorphic sites were identified as universal markers of drug resistance, with forty-seven
in PE/PPE regions and seventeen in functional genes. Mutations in genes such as cyp123, fadE36, gidB,
and ethA showed significant associations with resistance to various antibiotics. Notably, mutations
in cyp123 at codon position 279 were linked to resistance to ten antibiotics. The study highlighted
the role of PE/PPE and PE_PGRS genes in Mtb’s evolution towards a ‘mutator phenotype’. The
pathways of acquisition of mutations forming the epistatic landscape of MDR were discussed.
(4) CONCLUSIONS : This research identifies marker mutations across the Mtb genome associated with
MDR. The findings provide new insights into the molecular basis of MDR acquisition in Mtb, aiding
in the development of more effective diagnostics and treatments targeting these mutations to combat
MDR tuberculosis.
