title: Genome Analysis of the First Extensively Drug-Resistant (XDR) Mycobacterium tuberculosis in Malaysia Provides Insights into the Genetic Basis of Its Biology and Drug Resistance.
abstract: The outbreak of extensively drug-resistant tuberculosis (XDR-TB) has become an increasing problem in many TB-burdened countries. The underlying drug resistance mechanisms, including the genetic variation favored by selective pressure in the resistant population, are partially understood. Recently, the first case of XDR-TB was reported in Malaysia. However, the detailed genotype family and mechanisms of the formation of multiple drugs resistance are unknown. We sequenced the whole genome of the UM 1072388579 strain with a 2-kb insert-size library and combined with that from previously sequenced 500-bp-insert paired-end reads to produce an improved sequence with maximal sequencing coverage across the genome. In silico spoligotyping and phylogenetic analyses demonstrated that UM 1072388579 strain belongs to an ancestral-like, non-Beijing clade of East Asia lineage. This is supported by the presence of a number of lineage-specific markers, including fadD28, embA, nuoD and pks7. Polymorphism analysis showed that the drug-susceptibility profile is correlated with the pattern of resistance mutations. Mutations in drug-efflux pumps and the cell wall biogenesis pathway such as mmpL, pks and fadD genes may play an important role in survival and adaptation of this strain to its surrounding environment. In this work, fifty-seven putative promoter SNPs were identified. Among them, we identified a novel SNP located at -4 T allele of TetR/acrR promoter as an informative marker to recognize strains of East Asian lineage. Our work indicates that the UM 1072388579 harbors both classical and uncommon SNPs that allow it to escape from inhibition by many antibiotics. This study provides a strong foundation to dissect the biology and underlying resistance mechanisms of the first reported XDR M. tuberculosis in Malaysia.
authors.affiliation: Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Chee Sian
authors.initials: CS
authors.lastname: Kuan
authors.affiliation: Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Chai Ling
authors.initials: CL
authors.lastname: Chan
authors.affiliation: Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Su Mei
authors.initials: SM
authors.lastname: Yew
authors.affiliation: Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Yue Fen
authors.initials: YF
authors.lastname: Toh
authors.affiliation: Codon Genomics SB, Seri Kembangan, Selangor Darul Ehsan, Malaysia.
authors.forename: Jia-Shiun
authors.initials: JS
authors.lastname: Khoo
authors.affiliation: Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Chong
authors.affiliation: Codon Genomics SB, Seri Kembangan, Selangor Darul Ehsan, Malaysia.
authors.forename: Kok Wei
authors.initials: KW
authors.lastname: Lee
authors.affiliation: Codon Genomics SB, Seri Kembangan, Selangor Darul Ehsan, Malaysia.
authors.forename: Yung-Chie
authors.initials: YC
authors.lastname: Tan
authors.affiliation: Codon Genomics SB, Seri Kembangan, Selangor Darul Ehsan, Malaysia.
authors.forename: Wai-Yan
authors.initials: WY
authors.lastname: Yee
authors.affiliation: Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Yun Fong
authors.initials: YF
authors.lastname: Ngeow
authors.affiliation: Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Kee Peng
authors.initials: KP
authors.lastname: Ng
mesh_terms: D000995:Antitubercular Agents / Q000627:therapeutic use; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics*; D054908:Extensively Drug-Resistant Tuberculosis / Q000235:genetics / Q000382:microbiology*; D020869:Gene Expression Profiling; D016680:Genome, Bacterial; D006801:Humans; D008296:Malaysia; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000235:genetics* / Q000302:isolation & purification / Q000472:pathogenicity; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide
chemical_list: D000995:Antitubercular Agents