Jukic Marko, Rozman Kaja, Gobec Stanislav
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
Curr Med Chem. 2016;23(5):464-82. doi: 10.2174/0929867323666151231094854.
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.
临床实践中抗生素使用的增加以及细菌耐药性的出现，推动了新型抗菌药物研发的研究工作。未充分利用或全新的作用机制方法和生物学靶点尤其受到关注。十一异戊烯基焦磷酸合酶（UppS）是细菌细胞壁生物合成中的一种必需酶。尽管UppS是一个已验证的靶点，但药物中尚无选择性抑制剂。然而，已有几种天然底物类似物被报道并用于酶动力学研究或作为药理学探针。大多数小分子UppS抑制剂属于众所周知的双膦酸盐类，主要用于治疗骨吸收障碍。这类化合物中最有效的化合物的IC50为0.59 μM。本质上，这类化合物在抗菌药物设计中的选择性和适用性可能受到质疑。因此，开展了针对非双膦酸盐抑制剂的高通量筛选和虚拟筛选，并鉴定出了UppS的纳摩尔级抑制剂，其中一些对临床相关菌株具有抗菌活性。报道的支架结构属于IC50在100 nM范围内的四胺酸和四酮酸，以及IC50低至40 nM的二氢吡啶，均具有抗菌活性。芳基二酮酸也是具有耐甲氧西林金黄色葡萄球菌抗菌活性的有效抑制剂，变构抑制剂甲基异恶唑-4-甲酰胺（IC50，50 nM）对几种致病性肺炎链球菌菌株具有活性。氯米芬是一种著名的雌激素受体调节剂，据报道它能抑制UppS。尽管无法从所有这些数据中得出构效关系的结论，但这些化合物系列对抗生素领域做出了重要贡献。
