Nonsteroidal anti-inflammatory drug sensitizes Mycobacterium tuberculosis to endogenous and exogenous antimicrobials
Nonsteroidal anti-inflammatory drug sensitizes Mycobacterium tuberculosis to endogenous and exogenous antimicrobials
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DOI：
10.1073/pnas.1214188109
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发表时间：
2012-10-02
影响因子：
11.1
通讯作者：
Nathan, Carl F.
中科院分区：
文献类型：
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作者：
Gold, Ben;Pingle, Maneesh;Nathan, Carl F.
现有药物在根除患者体内结核分枝杆菌（Mtb）方面进展缓慢，未能在全球范围内控制结核病。一个原因可能是宿主条件损害了结核分枝杆菌的复制，降低了它对大多数抗感染药物的敏感性。我们设计了一种高通量筛选化合物，当结核分枝杆菌的复制被活性氮中间体（RNI）、酸、缺氧和脂肪酸碳源停止时，该化合物可以杀死结核分枝杆菌。在人血液中常规达到的浓度下，羟保泰松（OPB），一种廉价的抗炎药，对非复制型（NR）结核分枝杆菌具有选择性杀菌作用。其杀菌活性依赖于弱酸，RNI和脂肪酸可增强其杀菌活性。酸和RNI促进OPB的4-羟基化。所得的4-丁基-4-羟基-1（4-羟基苯基）-2-苯基吡唑烷-3，5-二酮（4-OH-OPB）杀死复制型和NR Mtb，包括对标准药物具有抗性的Mtb。4-OH-OPB耗尽黄素并与N-乙酰半胱氨酸和真菌硫醇形成共价加合物。4-OH-OPB与氧化剂和几种抗结核药物协同杀死Mtb。因此，阻断Mtb复制的条件修饰OPB并增强其杀灭作用。修饰的OPB杀死复制和NR Mtb，并对宿主衍生的和药用抗分枝杆菌剂敏感。
Existing drugs are slow to eradicate Mycobacterium tuberculosis (Mtb) in patients and have failed to control tuberculosis globally. One reason may be that host conditions impair Mtb's replication, reducing its sensitivity to most antiinfectives. We devised a high-throughput screen for compounds that kill Mtb when its replication has been halted by reactive nitrogen intermediates (RNIs), acid, hypoxia, and a fatty acid carbon source. At concentrations routinely achieved in human blood, oxyphenbutazone (OPB), an inexpensive anti-inflammatory drug, was selectively mycobactericidal to nonreplicating (NR) Mtb. Its cidal activity depended on mild acid and was augmented by RNIs and fatty acid. Acid and RNIs fostered OPB's 4-hydroxylation. The resultant 4-butyl-4-hydroxy-1( 4-hydroxyphenyl)-2-phenylpyrazolidine-3,5-dione (4-OH-OPB) killed both replicating and NR Mtb, including Mtb resistant to standard drugs. 4-OH-OPB depleted flavins and formed covalent adducts with N-acetyl-cysteine and mycothiol. 4-OH-OPB killedMtb synergistically with oxidants and several antituberculosis drugs. Thus, conditions that block Mtb's replication modify OPB and enhance its cidal action. Modified OPB kills both replicating and NR Mtb and sensitizes both to host-derived and medicinal antimycobacterial agents.