Repurposed dihydroorotate dehydrogenase inhibitors with efficacy against drug-resistant Acinetobacter baumannii.
Repurposed dihydroorotate dehydrogenase inhibitors with efficacy against drug-resistant Acinetobacter baumannii.
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DOI：
10.1073/pnas.2213116119
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发表时间：
2022-12-20
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
鲍曼不动杆菌的耐药菌株越来越普遍，导致发病率和死亡率增加，从而需要新类别的抗生素。在此，我们对鲍曼不动杆菌嘧啶生物合成酶二氢乳清酸脱氢酶 (AbDHODH) 作为治疗这种感染的潜在药物靶点进行了遗传和化学验证。我们证明 AbDHODH 对于鲍曼不动杆菌在宿主体内生存至关重要，并且我们鉴定了有效的、物种特异性的 AbDHODH 抑制剂，对高度耐药的鲍曼不动杆菌菌株具有活性。一种化合物对小鼠具有显着的保护作用。抑制剂结合 AbDHODH 的结构研究确定了抑制剂结合袋。这些数据支持开发针对 AbDHODH 的抗菌药物，用于治疗耐药鲍曼不动杆菌引起的感染。需要新的抗菌药物来治疗广泛耐药的鲍曼不动杆菌。从头嘧啶生物合成酶二氢乳清酸脱氢酶 (DHODH) 是疟疾和人类自身免疫性疾病的经过验证的药物靶点。我们提供的遗传证据表明鲍曼不动杆菌 DHODH (AbDHODH) 对于啮齿动物感染模型中细菌的存活至关重要。我们通过重新利用为我们的疟疾 DHODH 项目开发的约 450 个三唑并嘧啶/咪唑并嘧啶类似物的独特库，对 AbDHODH 进行化学验证，以鉴定 21 种对 AbDHODH 具有亚微摩尔活性的化合物。最有效的（DSM186，DHODH IC50 28 nM）对不同地区的鲍曼不动杆菌菌株（包括美罗培南耐药菌株）的最低抑制浓度≤1 µg/ml。具有较长体内半衰期的结构相关类似物 (DSM161) 在中性粒细胞减少小鼠大腿感染模型中具有显着的保护作用。令人鼓舞的是，在体外或体内均未发现对这些化合物产生耐药性。最后，AbDHODH 与 DSM186 结合的 X 射线结构解析至 1.4 Å 分辨率。这些数据支持 AbDHODH 作为开发治疗鲍曼不动杆菌和其他潜在高风险细菌感染的抗菌药物的药物靶点的潜力。
Drug-resistant strains of Acinetobacter baumannii are increasingly prevalent leading to increased morbidity and mortality, thereby dictating the need for new classes of antibiotics. Herein, we provide genetic and chemical validation of the A. baumannii pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (AbDHODH) as a potential drug target to treat this infection. We showed that AbDHODH is essential for A. baumannii to survive within the host, and we identified potent, species-specific inhibitors of AbDHODH active against highly drug-resistant A. baumannii strains. One compound conferred significant protection to mice. Structural studies of inhibitor-bound AbDHODH defined the inhibitor-binding pocket. These data support the development of antimicrobial agents directed against AbDHODH for the treatment of infections due to drug-resistant A. baumannii. New antimicrobials are needed for the treatment of extensively drug-resistant Acinetobacter baumannii. The de novo pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) is a validated drug target for malaria and human autoimmune diseases. We provide genetic evidence that A. baumannii DHODH (AbDHODH) is essential for bacterial survival in rodent infection models. We chemically validate the target by repurposing a unique library of ~450 triazolopyrimidine/imidazopyrimidine analogs developed for our malaria DHODH program to identify 21 compounds with submicromolar activity on AbDHODH. The most potent (DSM186, DHODH IC50 28 nM) had a minimal inhibitory concentration of ≤1 µg/ml against geographically diverse A. baumannii strains, including meropenem-resistant isolates. A structurally related analog (DSM161) with a long in vivo half-life conferred significant protection in the neutropenic mouse thigh infection model. Encouragingly, the development of resistance to these compounds was not identified in vitro or in vivo. Lastly, the X-ray structure of AbDHODH bound to DSM186 was solved to 1.4 Å resolution. These data support the potential of AbDHODH as a drug target for the development of antimicrobials for the treatment of A. baumannii and potentially other high-risk bacterial infections.
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结构引导的三唑嘧啶环取代基的铅优化鉴定出具有临床候选潜力的有效的恶性疟原虫二氢二酸二氢二酸脱氢酶抑制剂。
影响因子：
7.3
作者：
Coteron, Jose M.;Marco, Maria;Esquivias, Jorge;Deng, Xiaoyi;White, Karen L.;White, John;Koltun, Maria;El Mazouni, Farah;Kokkonda, Sreekanth;Katneni, Kasiram;Bhamidipati, Ravi;Shackleford, David M.;Angulo-Barturen, Inigo;Ferrer, Santiago B.;Belen Jimenez-Diaz, Maria;Gamo, Francisco-Javier;Goldsmith, Elizabeth J.;Charman, William N.;Bathurst, Ian;Floyd, David;Matthews, David;Burrows, Jeremy N.;Rathod, Pradipsinh K.;Charman, Susan A.;Phillips, Margaret A.
通讯作者：
Phillips, Margaret A.
三唑吡啶支架中的生物酶转化和置换，以鉴定抑制性恶性疟原虫二氢二酸疟原虫脱氢酶所需的最低药效团。
影响因子：
7.3
作者：
Marwaha, Alka;White, John;El Mazouni, Farah;Creason, Sharon A.;Kokkonda, Sreekanth;Buckner, Frederick S.;Charman, Susan A.;Phillips, Margaret A.;Rathod, Pradipsinh K.
通讯作者：
Rathod, Pradipsinh K.
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1016/s0969-2126(00)00077-0
发表时间：
2000-01-15
期刊：
STRUCTURE WITH FOLDING & DESIGN
影响因子：
--
作者：
Liu, SP;Neidhardt, EA;Clardy, J
通讯作者：
Clardy, J
影响因子：
7.3
作者：
Gujjar R;El Mazouni F;White KL;White J;Creason S;Shackleford DM;Deng X;Charman WN;Bathurst I;Burrows J;Floyd DM;Matthews D;Buckner FS;Charman SA;Phillips MA;Rathod PK
通讯作者：
Rathod PK