Nicotinamide Limits Replication of Mycobacterium tuberculosis and Bacille Calmette-Guérin Within Macrophages.
Nicotinamide Limits Replication of Mycobacterium tuberculosis and Bacille Calmette-Guérin Within Macrophages.
复制标题
烟酰胺限制巨噬细胞内结核分枝杆菌和卡介苗的复制。
DOI：
10.1093/infdis/jiz541
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
Hawn,ThomasR
中科院分区：
文献类型：
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作者：
Simmons,JasonD;Peterson,GlennaJ;Campo,Monica;Lohmiller,Jenny;Skerrett,ShawnJ;Tunaru,Sorin;Offermanns,Stefan;Sherman,DavidR;Hawn,ThomasR
需要新的抗微生物剂来治疗结核分枝杆菌。我们假设烟酰胺（NAM）和烟酸（NA）调节巨噬细胞功能以限制M。结核病复制除了他们的直接抗菌性能。两种化合物在7 H9肉汤中具有适度的活性，但只有NAM抑制巨噬细胞中的复制。令人惊讶的是，在巨噬细胞中，NAM和相关化合物吡嗪酰胺限制了卡介苗的生长，但不限制野生型牛分枝杆菌的生长，这两种细菌都缺乏功能性烟酰胺酶/吡嗪酰胺酶（PncA），从而使每种菌株在肉汤培养中对这些药物产生耐药性。有趣的是，NAM在感染了巨噬细胞的巨噬细胞中没有活性。编码pncA缺失的结核病突变体。我们得出结论，NAM和烟酸对感染的巨噬细胞的差异活性表明宿主特异性NAM靶点，而不是PncA依赖的直接抗菌特性。这些活性足以限制减毒BCG，但不能限制毒性野生型M。牛肝菌M.结核
Novel antimicrobials for treatment ofMycobacterium tuberculosisare needed. We hypothesized that nicotinamide (NAM) and nicotinic acid (NA) modulate macrophage function to restrictM. tuberculosisreplication in addition to their direct antimicrobial properties. Both compounds had modest activity in 7H9 broth, but only NAM inhibited replication in macrophages. Surprisingly, in macrophages NAM and the related compound pyrazinamide restricted growth of bacille Calmette-Guérin but not wild-typeMycobacterium bovis, which both lack a functional nicotinamidase/pyrazinamidase (PncA) rendering each strain resistant to these drugs in broth culture. Interestingly, NAM was not active in macrophages infected with a virulentM. tuberculosismutant encoding a deletion inpncA. We conclude that the differential activity of NAM and nicotinic acid on infected macrophages suggests host-specific NAM targets rather than PncA-dependent direct antimicrobial properties. These activities are sufficient to restrict attenuated BCG, but not virulent wild-typeM. bovisorM. tuberculosis.