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A genome-wide analysis of multidrug-resistant and extensively drug-resistant strains of Mycobacterium tuberculosis Beijing genotype

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Abstract

The Beijing genotype of Mycobacterium tuberculosis (MTB) is one of the most successful MTB lineages that has disseminated in the world. In China, the rate of multidrug-resistant (MDR) tuberculosis is significantly higher than the global average rate, and the Beijing genotype strains take the largest share of MDR strains. To study the genetic basis of the epidemiological findings that Beijing genotype has often been associated with tuberculosis outbreaks and drug resistance, we determined the genome sequences of four clinical isolates: two extensively drug resistant (XDR1219, XDR1221) and two multidrug resistant (WX1, WX3), using whole-genome sequencing. A large number of individual and shared SNPs of the four Beijing strains were identified. Our isolates harbored almost all classic drug resistance-associated mutations. The mutations responsible for drug resistance in the two XDR strains were consistent with the clinical quantitative drug resistance levels. COG analysis revealed that Beijing strains have significantly higher abundances of the mutations responsible for cell wall/membrane/envelope biogenesis (COG M), secondary metabolites biosynthesis, transport and catabolism (COG Q), lipid transport and metabolism (COG I) and defense mechanisms (COG V). The shared mutated genes of the four studied Beijing strains were significantly overrepresented in three DNA repair pathways. Our analyses promote the understanding of the genome polymorphism of the Beijing family strains and provide the molecular genetic basis for their wide dissemination capacity and drug resistance.

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Abbreviations

MTB:

Mycobacterium tuberculosis

MDR:

Multidrug resistant

COG:

Clusters of Orthologous Groups of proteins

TB:

Tuberculosis

RIF:

Rifampicin

INH:

Isoniazid

MDR-TB:

Multidrug-resistant tuberculosis

XDR-TB:

Extensively drug-resistant tuberculosis

FQs:

Fluoroquinolones

SNPs:

Single nucleotide polymorphisms

MIC:

Minimum inhibitory concentration

ORFs:

Open reading frames

TBDB:

TB Drug Resistance Mutation Database

STR:

Streptomycin

EMB:

Ethambutol

OFX:

Ofloxacin

QRDR:

Quinolone resistance-determining region

KAN:

Kanamycin

AMI:

Amikacin

CAP:

Capreomycin

MMR:

Mismatch repair

BER:

Base excision repair

NER:

Nucleotide excision repair

NHEJ:

Non-homologous end joining

WGS:

Whole-genome sequence

DIM:

Phthiocerol dimycocerosates

PGL:

Phenolglycolipids

ROS:

Reactive oxygen species

RNI:

Reactive nitrogen intermediates

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Acknowledgments

We thank Xuping Fu for many helpful discussions and for his help with the data analysis. This work received support from the National Key Technologies R & D Program of China during the twelfth Five-Year Plan period (No. 2013ZX10003003-004-002).

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Authors and Affiliations

  1. College of Life Sciences, Fudan University, Shanghai, 200433, People’s Republic of China

    Wei Wu, Lu Zhang, Guohua Yu, Honghai Wang & Yao Li

  2. Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, People’s Republic of China

    Huajun Zheng & Yongqiang Zhu

  3. Department of Medical Microbiology and Parasitology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, People’s Republic of China

    Zilu Wen & Shulin Zhang

  4. Wuxi Hospital of Infection Disease, Wuxi, 214005, Jiangsu, People’s Republic of China

    Hao Pei

  5. Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Medical School, Tongji University, Shanghai, 200433, People’s Republic of China

    Zhenling Cui & Zhongyi Hu

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  1. Wei Wu
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  2. Huajun Zheng
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Correspondence to Yao Li.

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Communicated by S. Hohmann.

Wei Wu and Huajun Zheng contributed equally to this work.

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Wu, W., Zheng, H., Zhang, L. et al. A genome-wide analysis of multidrug-resistant and extensively drug-resistant strains of Mycobacterium tuberculosis Beijing genotype. Mol Genet Genomics 288, 425–436 (2013). https://doi.org/10.1007/s00438-013-0758-4

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