Utility of the Biosynthetic Folate Pathway for Targets in Antimicrobial Discovery.
Utility of the Biosynthetic Folate Pathway for Targets in Antimicrobial Discovery.
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DOI：
10.3390/antibiotics3010001
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发表时间：
2014-01-21
期刊：
影响因子：
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通讯作者：
Bourne CR
中科院分区：
文献类型：
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作者：
Bourne CR
面对不断增长的耐药病原微生物，对新型抗菌药物的需求非常大。本综述将探讨基于当前使用的细菌生物合成叶酸途径内的多药理活性的抗菌治疗的潜力。叶酸代谢途径导致细胞功能所需前体的合成，并包含原核生物和真核生物共有的关键节点二氢叶酸还原酶（DHFR）。目前，DHFR 酶是抗癌治疗中甲氨蝶呤、抗菌药物甲氧苄啶以及抗原虫应用乙胺嘧啶的靶标。另一个抗叶酸靶点是二氢蝶酸合酶（DHPS），它是原核生物所独有的，因为它们无法通过饮食方式获取叶酸。它已被证明是历史最悠久的抗生素类别磺胺类药物的主要靶标，磺胺类药物与 DHFR 抑制剂具有协同作用。研究表明，大多数 DHPS 酶具有代谢利用磺胺类药物的能力，产生可能抑制需要产生二氢叶酸的下游酶的替代产物。最近的工作已经确定了磺酰胺类抗生素对真核酶墨蝶呤还原酶的脱靶作用，导致神经递质合成的改变。鉴于 DHFR 和 DHPS 的抑制剂旨在模拟其同源底物，其中包含共享的子结构，因此可以合理地预期这种“脱靶”效应。这些抑制剂还可能与叶酸途径中的酶邻居相互作用，这些酶邻居结合 DHFR 或 DHPS 酶的产物和/或类似子结构的底物。旨在评估多药理学的计算研究重申了这些结论。这导致了探索叶酸途径多个成员在调节细胞代谢方面的巨大效用的假设，并且包括原核特异性多药理学在抗菌应用中的有吸引力的能力。
The need for new antimicrobials is great in face of a growing pool of resistant pathogenic organisms. This review will address the potential for antimicrobial therapy based on polypharmacological activities within the currently utilized bacterial biosynthetic folate pathway. The folate metabolic pathway leads to synthesis of required precursors for cellular function and contains a critical node, dihydrofolate reductase (DHFR), which is shared between prokaryotes and eukaryotes. The DHFR enzyme is currently targeted by methotrexate in anti-cancer therapies, by trimethoprim for antibacterial uses, and by pyrimethamine for anti-protozoal applications. An additional anti-folate target is dihyropteroate synthase (DHPS), which is unique to prokaryotes as they cannot acquire folate through dietary means. It has been demonstrated as a primary target for the longest standing antibiotic class, the sulfonamides, which act synergistically with DHFR inhibitors. Investigations have revealed most DHPS enzymes possess the ability to utilize sulfa drugs metabolically, producing alternate products that presumably inhibit downstream enzymes requiring the produced dihydropteroate. Recent work has established an off-target effect of sulfonamide antibiotics on a eukaryotic enzyme, sepiapterin reductase, causing alterations in neurotransmitter synthesis. Given that inhibitors of both DHFR and DHPS are designed to mimic their cognate substrate, which contain shared substructures, it is reasonable to expect such “off-target” effects. These inhibitors are also likely to interact with the enzymatic neighbors in the folate pathway that bind products of the DHFR or DHPS enzymes and/or substrates of similar substructure. Computational studies designed to assess polypharmacology reiterate these conclusions. This leads to hypotheses exploring the vast utility of multiple members of the folate pathway for modulating cellular metabolism, and includes an appealing capacity for prokaryotic-specific polypharmacology for antimicrobial applications.