Genome-wide association studies of global Mycobacterium tuberculosis resistance to 13 antimicrobials in 10,228 genomes identify new resistance mechanisms.
Genome-wide association studies of global Mycobacterium tuberculosis resistance to 13 antimicrobials in 10,228 genomes identify new resistance mechanisms.
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全球结核分枝杆菌对10,228个基因组中的13种抗菌药的全基因组关联研究确定了新的耐药机制。
DOI：
10.1371/journal.pbio.3001755
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发表时间：
2022-08
期刊：
影响因子：
9.8
通讯作者：
Iqbal, Zamin
中科院分区：
文献类型：
--
作者：
Rodrigues, Camilla;Moore, David;Crook, Derrick W.;Cirillo, Daniela M.;Fowler, Philip W.;Iqbal, Zamin;Ismail, Nazir A.;Mistry, Nerges;Niemann, Stefan;Peto, Tim E. A.;Thwaites, Guy;Walker, A. Sarah;MWalker, Timothy;Wilson, Daniel J.;Earle, Sarah G.;Wilson, Daniel J.;Grazian, Clara;Walker, A. Sarah;Hunt, Martin;Knaggs, Jeff;Iqbal, Zamin
耐药结核病的出现是一个重大的全球公共卫生问题，威胁到控制该疾病的能力。全基因组测序作为一种快速诊断耐药感染的工具，可以改变患者的治疗和临床实践。虽然一些药物的耐药机制已被很好地理解，但可能仍有许多机制有待发现，特别是对于新药物和重新利用的药物。我们对全球10,228株结核分枝杆菌（MTB）进行了测序，并使用定量微滴板测定了13种抗菌素在2倍浓度稀释网格上的最低抑制浓度（MIC）。我们使用线性混合模型进行基于寡肽和寡核苷酸的全基因组关联研究，以发现目前尚未编目的抗性赋予机制。在二元耐药表型上使用MIC使新药物和再利用药物的样本遗传率提高了26%至37%，提高了我们检测新关联的能力。对于所有药物，我们都发现了与MIC相关的未编目变异，包括转录抑制因子Rv1219c（异烟肼）的Rv1218c启动子结合位点，裂解23S rRNA的vapBC20操纵子上游（利奈唑胺）和Cyp142活性位点编码α-螺旋的区域（氯法齐明，均p < 10−7.7）。我们观察到交叉抗性的人为信号可以根据MIC的相对效应大小来解开。我们的研究表明，非常大规模的研究能够大大提高我们对结核分枝杆菌抗微生物药物耐药性相关遗传变异的认识。耐药结核病的出现是一个重大的全球公共卫生问题，威胁到控制该疾病的能力。1万个结核分枝杆菌基因组的表型分型和测序确定了与对13种新的和重新利用的二线和一线药物的耐药性相关的以前未编目的遗传变异。
The emergence of drug-resistant tuberculosis is a major global public health concern that threatens the ability to control the disease. Whole-genome sequencing as a tool to rapidly diagnose resistant infections can transform patient treatment and clinical practice. While resistance mechanisms are well understood for some drugs, there are likely many mechanisms yet to be uncovered, particularly for new and repurposed drugs. We sequenced 10,228 Mycobacterium tuberculosis (MTB) isolates worldwide and determined the minimum inhibitory concentration (MIC) on a grid of 2-fold concentration dilutions for 13 antimicrobials using quantitative microtiter plate assays. We performed oligopeptide- and oligonucleotide-based genome-wide association studies using linear mixed models to discover resistance-conferring mechanisms not currently catalogued. Use of MIC over binary resistance phenotypes increased sample heritability for the new and repurposed drugs by 26% to 37%, increasing our ability to detect novel associations. For all drugs, we discovered uncatalogued variants associated with MIC, including in the Rv1218c promoter binding site of the transcriptional repressor Rv1219c (isoniazid), upstream of the vapBC20 operon that cleaves 23S rRNA (linezolid) and in the region encoding an α-helix lining the active site of Cyp142 (clofazimine, all p < 10−7.7). We observed that artefactual signals of cross-resistance could be unravelled based on the relative effect size on MIC. Our study demonstrates the ability of very large-scale studies to substantially improve our knowledge of genetic variants associated with antimicrobial resistance in M. tuberculosis. The emergence of drug resistant tuberculosis is a major global public health concern that threatens the ability to control the disease. Phenotyping and sequencing 10,000 Mycobacterium tuberculosis genomes identifies previously uncatalogued genetic variants associated with resistance to thirteen new and repurposed, second line and first line drugs.
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影响因子：
5.6
作者：
Cavazos, Alexandra;Prigozhin, Daniil M.;Alber, Tom
通讯作者：
Alber, Tom
影响因子：
16.6
作者：
Bradley P;Gordon NC;Walker TM;Dunn L;Heys S;Huang B;Earle S;Pankhurst LJ;Anson L;de Cesare M;Piazza P;Votintseva AA;Golubchik T;Wilson DJ;Wyllie DH;Diel R;Niemann S;Feuerriegel S;Kohl TA;Ismail N;Omar SV;Smith EG;Buck D;McVean G;Walker AS;Peto TE;Crook DW;Iqbal Z
通讯作者：
Iqbal Z
DOI：
10.1056/nejmoa1800474
发表时间：
2018-10-11
期刊：
The New England journal of medicine
影响因子：
--
作者：
CRyPTIC Consortium and the 100,000 Genomes Project;Allix-Béguec C;Arandjelovic I;Bi L;Beckert P;Bonnet M;Bradley P;Cabibbe AM;Cancino-Muñoz I;Caulfield MJ;Chaiprasert A;Cirillo DM;Clifton DA;Comas I;Crook DW;De Filippo MR;de Neeling H;Diel R;Drobniewski FA;Faksri K;Farhat MR;Fleming J;Fowler P;Fowler TA;Gao Q;Gardy J;Gascoyne-Binzi D;Gibertoni-Cruz AL;Gil-Brusola A;Golubchik T;Gonzalo X;Grandjean L;He G;Guthrie JL;Hoosdally S;Hunt M;Iqbal Z;Ismail N;Johnston J;Khanzada FM;Khor CC;Kohl TA;Kong C;Lipworth S;Liu Q;Maphalala G;Martinez E;Mathys V;Merker M;Miotto P;Mistry N;Moore DAJ;Murray M;Niemann S;Omar SV;Ong RT;Peto TEA;Posey JE;Prammananan T;Pym A;Rodrigues C;Rodrigues M;Rodwell T;Rossolini GM;Sánchez Padilla E;Schito M;Shen X;Shendure J;Sintchenko V;Sloutsky A;Smith EG;Snyder M;Soetaert K;Starks AM;Supply P;Suriyapol P;Tahseen S;Tang P;Teo YY;Thuong TNT;Thwaites G;Tortoli E;van Soolingen D;Walker AS;Walker TM;Wilcox M;Wilson DJ;Wyllie D;Yang Y;Zhang H;Zhao Y;Zhu B
通讯作者：
Zhu B
影响因子：
--
作者：
Arenas NE;Salazar LM;Soto CY;Vizcaíno C;Patarroyo ME;Patarroyo MA;Gómez A
通讯作者：
Gómez A
DOI：
10.1164/rccm.201510-2091oc
发表时间：
2016-09-01
影响因子：
24.7
作者：
Farhat, Maha R.;Sultana, Razvan;Murray, Megan
通讯作者：
Murray, Megan