十一异戊二烯焦磷酸合成酶抑制剂作为潜在的抗菌药物研究的新进展

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.

Cite this article as:

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