Kanji Akbar, Hasan Rumina, Zaver Ambreen, Ali Asho, Imtiaz Kehkashan, Ashraf Mussarat, Clark Taane G, McNerney Ruth, Shafiq Samreen, Hasan Zahra
Department of Pathology and Laboratory Medicine, The Aga Khan University, Stadium Road, Karachi 74800, Pakistan.
Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK; Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK.
Int J Mycobacteriol. 2016 Dec;5 Suppl 1:S97-S98. doi: 10.1016/j.ijmyco.2016.09.064. Epub 2016 Nov 22.
Extensively drug-resistant tuberculosis (XDR-TB) has emerged as one of the biggest threats to public health and TB control programs worldwide. XDR-TB is caused by Mycobacterium tuberculosis (MTB) strains resistant to rifampin and isoniazid, as well as to a fluoroquinolone and to at least one injectable aminoglycoside. Drug resistance in MTB has primarily been associated with single nucleotide polymorphisms (SNPs) in particular genes. However, it has also been shown that efflux pumps may play a role in resistance of MTB. Upregulation of drug efflux pumps can decrease the intracellular concentration of drugs and reduce their efficacy.
Whole genome sequencing was performed on 32 XDR-TB clinical isolates. Sequence data were used to investigate SNPs in efflux pump genes as compared with the H37Rv reference genome.
Of the XDR MTB strains, eight (21.62%) were wild type for rpsL, rrs (500 region), and gidB genes, but had non-synonymous (ns) SNPs (aspartic acid to histidine) in the drrA efflux pump gene at position 3273138. Three of eight (37.5%) XDR MTB strains, wild type for rpsL, rrs (500 region), gidB, and gyrB genes were phenotypically streptomycin sensitive and five (62.5%) XDR MTB strains were streptomycin resistant, while all XDR MTB strains, wild type for rpsL, rrs, gidB, and gyrB genes were resistant to fluoroquinolone (ofloxacin) and ethambutol. In addition, three XDR MTB strains wild type for rpsL, rrs, gidB, and drrA genes showed nsSNPs (isoleucine to valine) in the major facilitator superfamily, Rv1634 efflux pump gene at position 1839306.
Our data show an nsSNP in the drrA efflux pump gene that may result in upregulation of drug efflux mechanisms in MTB strains. It is therefore imperative to understand the mechanism of efflux and its role in drug resistance, which will enable the identification of new drug targets and development of new drug regimens to counteract the drug efflux mechanism of MTB.
广泛耐药结核病（XDR-TB）已成为全球公共卫生和结核病控制项目面临的最大威胁之一。XDR-TB由对利福平、异烟肼、氟喹诺酮类药物以及至少一种注射用氨基糖苷类药物耐药的结核分枝杆菌（MTB）菌株引起。MTB中的耐药性主要与特定基因中的单核苷酸多态性（SNP）有关。然而，也有研究表明外排泵可能在MTB的耐药性中发挥作用。药物外排泵的上调可降低细胞内药物浓度并降低其疗效。
对32株XDR-TB临床分离株进行全基因组测序。与H37Rv参考基因组相比，序列数据用于研究外排泵基因中的SNP。
在XDR MTB菌株中，8株（21.62%）rpsL、rrs（500区域）和gidB基因是野生型，但在drrA外排泵基因第3273138位有非同义（ns）SNP（天冬氨酸突变为组氨酸）。8株XDR MTB菌株中，3株（37.5%）rpsL、rrs（500区域）、gidB和gyrB基因是野生型，表型上对链霉素敏感，5株（62.5%）XDR MTB菌株对链霉素耐药，而所有rpsL、rrs、gidB和gyrB基因是野生型的XDR MTB菌株对氟喹诺酮类药物（氧氟沙星）和乙胺丁醇耐药。此外，3株rpsL、rrs、gidB和drrA基因是野生型的XDR MTB菌株在主要易化子超家族Rv1634外排泵基因第1839306位显示有nsSNP（异亮氨酸突变为缬氨酸）。
我们的数据显示drrA外排泵基因中的一个nsSNP可能导致MTB菌株中药物外排机制上调。因此，必须了解外排机制及其在耐药性中的作用，这将有助于识别新的药物靶点并开发新的药物方案以对抗MTB的药物外排机制。
