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Pyrazinamide resistance of novel mutations in pncA and their dynamic behavior

机译：PNCA中新型突变的吡嗪酰胺抗性及其动力学行为

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Pyrazinamide (PZA) is one of the essential anti-mycobacterium drugs, active against non-replicating Mycobacterium tuberculosis (MTB) isolates. PZA is converted into its active state, called pyrazinoic acid (POA), by action of pncA encoding pyrazinamidase (PZase). In the majority of PZA-resistance isolates, pncA harbored mutations in the coding region. In our recent report, we detected a number of novel variants in PZA-resistance (PZA ~(R) ) MTB isolates, whose resistance mechanisms were yet to be determined. Here we performed several analyses to unveil the PZA ~(R) mechanism of R123P, T76P, G150A, and H71R mutants (MTs) through molecular dynamics (MD) simulations. In brief, culture positive MTB isolates were subjected to PZA susceptibility tests using the WHO recommended concentration of PZA (100 μg ml ~(?1) ). The PZA ~(R) samples were screened for mutations in pncA along sensitive isolates through polymerase chain reactions and sequencing. A large number of variants (GeneBank accession no. MH461111), including R123P, T76P, G150A, and H71R, have been spotted in more than 70% of isolates. However, the mechanism of PZA ~(R) for mutants (MTs) R123P, T76P, G150A, and H71R was unknown. For the MTs and native PZase structures (WT), thermodynamic properties were compared using molecular dynamics simulations for 100 ns. The MTs structural activity was compared to the WT. Folding effect and pocket volume variations have been detected when comparing between WT and MTs. Geometric matching further confirmed the effect of R123P, T76P, G150A, and H71R mutations on PZase dynamics, making them vulnerable for activating the pro-drug into POA. This study offers a better understanding for management of PZA ~(R) TB. The results may be used as alternative diagnostic tools to infer PZA resistance at a structural dynamics level.
机译：吡嗪酰胺（PZA）是必不可少的抗分子药物之一，反对非复制分枝杆菌（MTB）分离株。通过PNCA编码吡嗪酰胺酶（PZ酶）的作用，PZA转化为称为吡嗪酸（POA）的活性状态。在大多数PZA抗性分离物中，PNCA在编码区中的突变突变。在我们最近的报告中，我们在PZA电阻（PZA〜（R））MTB隔离物中检测了许多新型变体，其电阻机制尚未确定。在这里，我们通过分子动力学（MD）模拟来进行几种分析以推出R123P，T76P，G150A和H71R突变体（MTS）的PZA〜（R）机制。简而言之，使用推荐的PZA浓度（100μgml〜（β1））对培养阳性MTB分离物进行PZA易感试验。通过聚合酶链反应和测序沿敏感分离液筛选PNCA中的突变的PZA〜（R）样品。大量变体（GeneBank登录号MH461111），包括R123P，T76P，G150A和H71R，已发现超过70％的分离物。然而，突变体（MTS）R123P，T76P，G150A和H71R的PZA〜（R）的机制未知。对于MTS和Native Pzase结构（WT），使用100ns的分子动力学模拟比较热力学性质。将MTS结构活性与WT进行比较。在比较WT和MTS时，检测到折叠效果和口袋体积变化。几何匹配进一步证实了R123P，T76P，G150A和H71R突变对PZA酶动态的影响，使得它们易于将药物激活到POA中。本研究为PZA〜（R）结核病的管理提供了更好的理解。结果可以用作替代诊断工具，以推断结构动力学水平的PZA电阻。

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