摘要
扩大抗生素在临床实践和产生耐药性的使用推动了新型抗菌药物的开发研究。未开发的或完全新颖的机制方法和生物目标引起了研究者的兴趣。十一异戊二烯焦磷酸合成酶(UPPS)是细菌细胞壁的生物合成的关键酶。虽然UPPS是一个有效的靶点,但目前并没有选择性的抑制剂。然而,几个天然底物类似物已被报道并用于酶动力学研究,或作为药理学探针。小分子UPPS抑制剂属于双膦酸盐类药物,主要用于治疗骨吸收障碍的患者。这一类的最有效的化合物IC50值为0.59μM 。从本质上讲,该抗菌药物的选择性和适用性应该受到质疑。因此,对于非二磷酸盐抑制剂进行高通量虚拟放映测试,并能纳摩尔抑制剂进行了鉴定,对临床相关菌株的抗菌活性进行检测。报道的scaffolds属于tetramic和 tetronic acids ,IC50在 100-nM 范围内,当其为二氢吡啶时,IC50下降为40 nm,但他们都具有抗菌活性。芳香二酮酸也是具有MRSA抗菌活性的有效抑制剂,它与变构抑制剂methylisoxazole-4-carboxamide(IC50,50 nm)对某些致病性肺炎链球菌都具有活性。克罗米酚是一种著名的雌激素受体调节剂,并被报道能抑制UPPS。虽然不能从这些数据中得出结构活性之间的关系,这些化合物对抗生素领域具有重要贡献。
关键词: 十一异戊二烯焦磷酸合成酶,类异戊二烯,肽聚糖,细胞壁,诱导抑制剂、抗菌药物、抗生素。
Current Medicinal Chemistry
Title:Recent Advances in the Development of Undecaprenyl Pyrophosphate Synthase Inhibitors as Potential Antibacterials
Volume: 23 Issue: 5
Author(s): Marko Jukič, Kaja Rožman and Stanislav Gobec
Affiliation:
关键词: 十一异戊二烯焦磷酸合成酶,类异戊二烯,肽聚糖,细胞壁,诱导抑制剂、抗菌药物、抗生素。
摘要: Expanding antibiotic use in clinical practice and emergence of bacterial resistance are fueling research efforts for the development of novel antibacterials. Underexploited or completely novel mechanistic approaches and biological targets are of especial interest. Undecaprenyl pyrophosphate synthase (UppS) is an essential enzyme in the biosynthesis of the bacterial cell wall. Although UppS is a validated target, no selective inhibitors occur in materia medica. Nevertheless, several native substrate analogues have been reported and used in enzyme kinetics studies or as pharmacological probes. The majority of small-molecule UppS inhibitors belong to the well-known class of bisphosphonates that are primarily used for treatment of bone resorption disorders. The most potent compound of this class has an IC50 of 0.59 µM. Inherently, the selectivity and suitability of such compounds for antimicrobial drug design can be questioned. Therefore, highthroughput and virtual screenings for non-bisphosphonate inhibitors were performed, and nanomolar inhibitors of UppS were identified, some with antimicrobial activities towards clinically relevant strains. The reported scaffolds belong to tetramic and tetronic acids with IC50 in the 100-nM range, and to dihydropyridines with IC50 down to 40 nM, all with antibacterial activity. Aryl-diketo acids are also potent inhibitors with MRSA antimicrobial activity, with the allosteric inhibitor methylisoxazole-4-carboxamide (IC50, 50 nM) active on several pathogenic Streptococcus pneumoniae strains. Clomiphene is a well-known oestrogen receptor modulator, and it has been reported to inhibit UppS. Although conclusions on the structure activity relationships cannot be drawn from all these data, these compound series represent an important contribution to the field of antibiotics.
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Marko Jukič, Kaja Rožman and Stanislav Gobec , Recent Advances in the Development of Undecaprenyl Pyrophosphate Synthase Inhibitors as Potential Antibacterials, Current Medicinal Chemistry 2016; 23 (5) . https://dx.doi.org/10.2174/0929867323666151231094854
DOI https://dx.doi.org/10.2174/0929867323666151231094854 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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