Imidazopyridine Compounds Inhibit Mycobacterial Growth by Depleting ATP Levels.
Imidazopyridine Compounds Inhibit Mycobacterial Growth by Depleting ATP Levels.
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DOI：
10.1128/aac.02439-17
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发表时间：
2018-06
影响因子：
4.9
通讯作者：
Parish T
中科院分区：
文献类型：
--
作者：
O'Malley T;Alling T;Early JV;Wescott HA;Kumar A;Moraski GC;Miller MJ;Masquelin T;Hipskind PA;Parish T
咪唑吡啶类药物具有良好的体内外抗结核活性，是一类很有前途的新型抗结核药物。我们分离出对代表性咪唑吡啶耐药的结核分枝杆菌突变体；突变体在MIC上有很大的变化（约20倍）。全基因组测序揭示了Rv1339的突变，Rv1339是一种功能未知的假设蛋白。我们从该系列中分离出对另外三种化合物具有抗性的突变体；从其中两种化合物中分离出的耐药突变体在Rv1339中具有单核苷酸多态性，从第三种化合物中分离出的耐药突变体在QcrB中具有单核苷酸多态性，QcrB是该系列的拟靶点。所有菌株均对两种化合物耐药，且携带QcrB T313I突变的菌株对所有测试的咪唑吡啶衍生物耐药，证实了交叉耐药。通过监测pH稳态和ATP生成，我们证实了该系列化合物靶向QcrB；咪唑吡啶破坏了pH稳态并耗尽了ATP，进一步证明了其对电子传递链的影响。一种具有代表性的化合物对复制细菌具有抑菌作用，与对QcrB的作用模式一致。该系列具有狭窄的抑制谱，对其他细菌种类没有活性。未发现与其它正在开发的抗结核药物有协同作用或拮抗作用。总之，我们的数据支持咪唑吡啶系列通过抑制QcrB来减少ATP生成的假设。
The imidazopyridines are a promising new class of antitubercular agents with potent activity in vitro and in vivo. We isolated mutants of Mycobacterium tuberculosis resistant to a representative imidazopyridine; the mutants had large shifts (>20-fold) in MIC. Whole-genome sequencing revealed mutations in Rv1339, a hypothetical protein of unknown function. We isolated mutants resistant to three further compounds from the series; resistant mutants isolated from two of the compounds had single nucleotide polymorphisms in Rv1339 and resistant mutants isolated from the third compound had single nucleotide polymorphisms in QcrB, the proposed target for the series. All the strains were resistant to two compounds, regardless of the mutation, and a strain carrying the QcrB T313I mutation was resistant to all of the imidazopyridine derivatives tested, confirming cross-resistance. By monitoring pH homeostasis and ATP generation, we confirmed that compounds from the series were targeting QcrB; imidazopyridines disrupted pH homeostasis and depleted ATP, providing further evidence of an effect on the electron transport chain. A representative compound was bacteriostatic against replicating bacteria, consistent with a mode of action against QcrB. The series had a narrow inhibitory spectrum, with no activity against other bacterial species. No synergy or antagonism was seen with other antituberculosis drugs under development. In conclusion, our data support the hypothesis that the imidazopyridine series functions by reducing ATP generation via inhibition of QcrB.