Drug screening to identify compounds to act as co-therapies for the treatment of Burkholderia species.
Drug screening to identify compounds to act as co-therapies for the treatment of Burkholderia species.
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DOI：
10.1371/journal.pone.0248119
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发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Harmer NJ
中科院分区：
文献类型：
--
作者：
Barker S;Harding SV;Gray D;Richards MI;Atkins HS;Harmer NJ
类鼻疽伯克霍尔德氏菌是一种生活在土壤中的生物，分布于整个热带地区。它是类鼻疽病的病原体，这种疾病据信每年造成89，000人死亡。它对许多抗生素具有天然耐药性，需要至少两周的头孢他啶、亚胺培南或美罗培南静脉治疗，然后口服复方新诺明6个月。这给大多数疾病发生的主要中等收入国家带来了巨大的治疗负担。我们已经建立了一个高通量的测定化合物，可以用作一个共同的治疗，以加强头孢他啶的效果，使用相关的非致病性细菌伯克霍尔德氏菌作为替代。测定的优化得到0.68的Z'因子。我们筛选了61，250种化合物的库，并鉴定了29种pIC 50（-log 10（IC 50））大于5的化合物。详细的调查使我们能够选择六种“最好的”化合物，其中包括许可药物氯氧嘧啶。共处理B。与仅用头孢他啶处理相比，用头孢他啶和氯氧嘧啶处理的Thailandensis在48小时内使可培养细胞数减少两个数量级。使用可商购的化合物进行围绕氯喹的命中扩展。对结构的微小修改消除了活性，这表明氯氧喹啉可能对特定目标起作用。最后，一项初步研究表明，氯氧嘧啶可作为一种联合疗法，增强头孢他啶对B的作用。假鼻疽该方法成功地鉴定了用于耐药性革兰氏阴性细菌物种的潜在联合疗法。我们的检测方法可以更广泛地用于辅助化疗，以治疗由这些细菌引起的感染。
Burkholderia pseudomallei is a soil-dwelling organism present throughout the tropics. It is the causative agent of melioidosis, a disease that is believed to kill 89,000 people per year. It is naturally resistant to many antibiotics, requiring at least two weeks of intravenous treatment with ceftazidime, imipenem or meropenem followed by 6 months of orally delivered co-trimoxazole. This places a large treatment burden on the predominantly middle-income nations where the majority of disease occurs. We have established a high-throughput assay for compounds that could be used as a co-therapy to potentiate the effect of ceftazidime, using the related non-pathogenic bacterium Burkholderia thailandensis as a surrogate. Optimization of the assay gave a Z’ factor of 0.68. We screened a library of 61,250 compounds and identified 29 compounds with a pIC50 (-log10(IC50)) greater than five. Detailed investigation allowed us to down select to six “best in class” compounds, which included the licensed drug chloroxine. Co-treatment of B. thailandensis with ceftazidime and chloroxine reduced culturable cell numbers by two orders of magnitude over 48 hours, compared to treatment with ceftazidime alone. Hit expansion around chloroxine was performed using commercially available compounds. Minor modifications to the structure abolished activity, suggesting that chloroxine likely acts against a specific target. Finally, an initial study demonstrates the utility of chloroxine to act as a co-therapy to potentiate the effect of ceftazidime against B. pseudomallei. This approach successfully identified potential co-therapies for a recalcitrant Gram-negative bacterial species. Our assay could be used more widely to aid in chemotherapy to treat infections caused by these bacteria.
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影响因子：
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作者：
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通讯作者：
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作者：
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DOI：
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发表时间：
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期刊：
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影响因子：
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作者：
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作者：
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通讯作者：
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