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首页> 外文期刊>Journal of bacteriology >Metallochaperones Are Needed for Mycobacterium tuberculosis and Escherichia coli Nicotinamidase-Pyrazinamidase Activity
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Metallochaperones Are Needed for Mycobacterium tuberculosis and Escherichia coli Nicotinamidase-Pyrazinamidase Activity

机译：核细胞结核病和大肠杆菌烟草酰胺酶 - 吡嗪酰胺酶活性所需的金属体酮

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Mycobacterium tuberculosis nicotinamidase-pyrazinamidase (PZAse) is a metalloenzyme that catalyzes conversion of nicotinamide-pyrazinamide to nicotinic acid-pyrazinoic acid. This study investigated whether a metallochaperone is required for optimal PZAse activity. M. tuberculosis and Escherichia coli PZAses (PZAse-MT and PZAse-EC, respectively) were inactivated by metal depletion (giving PZAse-MT–Apo and PZAse-EC–Apo). Reactivation with the E. coli metallochaperone ZnuA or Rv2059 (the M. tuberculosis analog) was measured. This was repeated following proteolytic and thermal treatment of ZnuA and Rv2059. The CDC1551 M. tuberculosis reference strain had the Rv2059 coding gene knocked out, and PZA susceptibility and the pyrazinoic acid (POA) efflux rate were measured. ZnuA (200?μM) achieved 65% PZAse-EC–Apo reactivation. Rv2059 (1?μM) and ZnuA (1?μM) achieved 69% and 34.3% PZAse-MT–Apo reactivation, respectively. Proteolytic treatment of ZnuA and Rv2059 and application of three (but not one) thermal shocks to ZnuA significantly reduced the capacity to reactivate PZAse-MT–Apo. An M. tuberculosis Rv2059 knockout strain was Wayne positive and susceptible to PZA and did not have a significantly different POA efflux rate than the reference strain, although a trend toward a lower efflux rate was observed after knockout. The metallochaperone Rv2059 restored the activity of metal-depleted PZAse in vitro . Although Rv2059 is important in vitro , it seems to have a smaller effect on PZA susceptibility in vivo. It may be important to mechanisms of action and resistance to pyrazinamide in M. tuberculosis. Further studies are needed for confirmation. IMPORTANCE Tuberculosis is an infectious disease caused by the bacterium Mycobacterium tuberculosis and remains one of the major causes of disease and death worldwide. Pyrazinamide is a key drug used in the treatment of tuberculosis, yet its mechanism of action is not fully understood, and testing strains of M. tuberculosis for pyrazinamide resistance is not easy with the tools that are presently available. The significance of the present research is that a metallochaperone-like protein may be crucial to pyrazinamide’s mechanisms of action and of resistance. This may support the development of improved tools to detect pyrazinamide resistance, which would have significant implications for the clinical management of patients with tuberculosis: drug regimens that are appropriately tailored to the resistance profile of a patient’s individual strain lead to better clinical outcomes, reduced onward transmission of infection, and reduction of the development of resistant strains that are more challenging and expensive to treat.
机译：结核分枝杆菌烟氨基酰胺酶 - 吡嗪酰胺酶（PZ酶）是一种催化烟酰胺 - 吡嗪酰胺转化为烟酸 - 吡唑基酰基酸的金属酶。本研究研究了最佳禁止酶活性是否需要金属体体。 M.结核病和大肠杆菌蛋白酶（分别通过金属耗尽灭活（Pzase-mt-apo和pzase-Ec-apo）灭活。测量与大肠杆菌金属体酮Znua或rv2059（M.结核菌分类似物）的再活化。在Znua和RV2059的蛋白水解和热处理之后重复这一点。 CDC1551M.Tuberculosis参考菌株具有RV2059编码基因敲除，并测量PZA易感性和吡唑酸（POA）排出速率。 Znua（200？μm）达到65％的Pzase-EC-APO再激活。 RV2059（1？μm）和Znua（1？μm）分别达到69％和34.3％的Pzase-Mt-Apo Reactivation。 Znua和RV2059的蛋白水解治疗和三种（但不是一个）热冲击到Znua的热冲击显着降低了重新激活pzase-mt-apo的能力。对于PZA，肺结核酸率RV2059敲除菌株是阳性和易感的POA流出率而不是参考应变，尽管在敲除后观察到较低的渗透率的趋势。 Metallochaperone RV2059恢复了体外金属耗尽的Pzase的活性。虽然RV2059在体外很重要，但它似乎对体内PZA易感性效果较小。对淀粉嗪酰胺的作用和抗性的机制可能是重要的。确认需要进一步研究。重要性结核病是由细菌结核菌菌造成的传染病，并且仍然是全世界疾病和死亡的主要原因之一。吡嗪酰胺是一种用于治疗结核病的关键药物，但其作用机制尚未完全理解，并且目前可获得的工具不容易达到吡嗪酰胺抗性的肺结核的测试菌株。本研究的重要性是金属体蛋白样蛋白质对吡嗪酰胺的作用机制至关重要。这可能支持改进的工具来检测吡嗪酰胺抗性，这对结核病患者的临床管理产生重大影响：适当地定制对患者个体菌株的抗性曲线的药物方案导致更好的临床结果，减少感染的传播，以及减少更具挑战性和昂贵的抗性菌株的发展。

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