Pyrazinamide Resistance Is Caused by Two Distinct Mechanisms: Prevention of Coenzyme A Depletion and Loss of Virulence Factor Synthesis.
Pyrazinamide Resistance Is Caused by Two Distinct Mechanisms: Prevention of Coenzyme A Depletion and Loss of Virulence Factor Synthesis.
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DOI：
10.1021/acsinfecdis.6b00070
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发表时间：
2016-09-09
影响因子：
5.3
通讯作者：
Dick T
中科院分区：
文献类型：
--
作者：
Gopal P;Yee M;Sarathy J;Low JL;Sarathy JP;Kaya F;Dartois V;Gengenbacher M;Dick T
吡津酰胺(PZA)是结核病(TB)一线和二线治疗的关键成分，但其作用机制在很大程度上仍是一个谜。我们对牛分枝杆菌卡介苗耐药突变株进行了遗传筛选，并对26株耐药菌株进行了全基因组测序。我们没有在所提出的候选靶标脂肪酸合成酶I和核糖体蛋白S1中发现突变，而是在两种途径中发现了与耐药性相关的突变：参与合成必需的酰基载体辅酶A(CoA)的天冬氨酸脱羧酶pAND的错义突变，以及参与合成毒力因子邻苯二甲酸二肌油酸酯(PDIM)的体外非必需聚酮合成酶基因Mas和PPSA-E的移码突变。对POA的两个结构类似物烟酸和苯甲酸的交叉抗性的探索表明，这两个类似物与POA具有相同的PDIM-但不具有CoA相关的作用机制。我们证明了POA耗尽野生型细菌中的CoA，这是通过pand突变来防止的。对10株耐POA结核分枝杆菌H37Rv菌株进行测序证实，至少存在两种不同的耐药机制。通过在体外失去毒力因子而产生的耐药性可能解释了为什么在PZA耐药的临床分离株中，除了前药物转换酶的突变之外，缺乏明确的分子模式。POA对毒力途径的明显干扰可能有助于该药物在体内的出色疗效，而不是其适度的体外效力。
Pyrazinamide (PZA) is a critical component of first- and second-line treatments of tuberculosis (TB), yet its mechanism of action largely remains an enigma. We carried out a genetic screen to isolate Mycobacterium bovis BCG mutants resistant to pyrazinoic acid (POA), the bioactive derivative of PZA, followed by whole genome sequencing of 26 POA resistant strains. Rather than finding mutations in the proposed candidate targets fatty acid synthase I and ribosomal protein S1, we found resistance conferring mutations in two pathways: missense mutations in aspartate decarboxylase panD, involved in the synthesis of the essential acyl carrier coenzyme A (CoA), and frameshift mutations in the vitro nonessential polyketide synthase genes mas and ppsA-E, involved in the synthesis of the virulence factor phthiocerol dimycocerosate (PDIM). Probing for cross resistance to two structural analogs of POA, nicotinic acid and benzoic acid, showed that the analogs share the PDIM- but not the CoA-related mechanism of action with POA. We demonstrated that POA depletes CoA in wild-type bacteria, which is prevented by mutations in panD. Sequencing 10 POA-resistant Mycobacterium tuberculosis H37Rv isolates confirmed the presence of at least 2 distinct mechanisms of resistance to the drug. The emergence of resistance through the loss of a virulence factor in vitro may explain the lack of clear molecular patterns in PZA-resistant clinical isolates, other than mutations in the prodrug-converting enzyme. The apparent interference of POA with virulence pathways may contribute to the drug’s excellent in vivo efficacy compared to its modest in vitro potency.
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Bedaquiline和吡嗪酰胺治疗反应受肺病变异质性的影响，感染了C3HEB/FEJ小鼠。
影响因子：
5.3
作者：
Irwin SM;Prideaux B;Lyon ER;Zimmerman MD;Brooks EJ;Schrupp CA;Chen C;Reichlen MJ;Asay BC;Voskuil MI;Nuermberger EL;Andries K;Lyons MA;Dartois V;Lenaerts AJ
通讯作者：
Lenaerts AJ
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
影响因子：
4.9
作者：
Lanoix, Jean-Philippe;Tasneen, Rokeya;Nuermberger, Eric
通讯作者：
Nuermberger, Eric
影响因子：
3.7
作者：
Ali A;Hasan Z;McNerney R;Mallard K;Hill-Cawthorne G;Coll F;Nair M;Pain A;Clark TG;Hasan R
通讯作者：
Hasan R
DOI：
10.1073/pnas.0610634104
发表时间：
2007-03-20
影响因子：
11.1
作者：
Jain, Madhulika;Petzold, Christopher J.;Cox, Jeffery S.
通讯作者：
Cox, Jeffery S.