Tran-Nguyen Viet-Khoa, Prasad Rajendra, Falson Pierre, Boumendjel Ahcene
Department of Molecular Pharmacochemistry (DPM), UMR 5063, Grenoble Alpes University, F-38041 Grenoble. France.
School of Life Sciences, Jawaharlal Nehru University, 110067 New Delhi. India.
Curr Med Chem. 2017;24(30):3242-3253. doi: 10.2174/0929867324666170523102244.
The multicomponent primary active ATP-binding cassette transporter Cdr1p in the structure of the pathogenic yeast Candida albicans is among the culprits of antifungal agent resistance reported in recent decades. So far, various potential novel inhibitors/ modulators of this protein have been purified, synthesized, and biologically tested, with results showing their ability to effectively reverse CaCdr1p-mediated drug resistance phenomenon. These compounds are of diverse origins, possess non-identical structural features and adopt different mechanisms of action.
A structured search of chemical features and mechanisms of studied modulators of CaCdr1p was carried out using both original research publications and review articles. The nature of possible inhibitory mechanisms against the pump was analyzed in relation to the structure and the activity of the transporter. A process of summarizing modulatory spectra of the listed compounds against 2 other efflux pumps of Candida albicans namely Cdr2p and Mdr1p was also conducted, during which selective inhibitors of Cdr1p were revealed.
In this article, 6 possible mechanisms with which a molecule can manifest their activity against the efflux pump are described, and a list of nearly 50 CaCdr1p modulators found in literatures along with their respective mechanism(s) (if already identified) is provided, summarizing the results obtained so far in the search of new inhibitors of the drug extrusion transporter that can enhance the potency of commonly used antifungal agents. A table of inhibitory spectra of the listed compounds against Cdr1p, Cdr2p and Mdr1p is also given, with several selective modulators of Cdr1p finally indicated.
The findings of this review contribute to future studies regarding CaCdr1p and its modulators by summarizing the results obtained so far on this emerging issue of health sciences. Further research concerning novel compounds capable of inhibiting Cdr1p needs to be carried out in hopes of completing the lists provided in this article.
致病性白色念珠菌结构中的多组分原发性活性ATP结合盒转运蛋白Cdr1p是近几十年来报道的抗真菌药物耐药性的罪魁祸首之一。到目前为止，该蛋白的各种潜在新型抑制剂/调节剂已被纯化、合成并进行生物学测试，结果表明它们能够有效逆转CaCdr1p介导的耐药现象。这些化合物来源多样，具有不同的结构特征并采用不同的作用机制。
利用原始研究出版物和综述文章，对已研究的CaCdr1p调节剂的化学特征和作用机制进行结构化搜索。结合转运蛋白的结构和活性，分析了针对该泵可能的抑制机制的性质。还对列出的化合物针对白色念珠菌的另外两种外排泵Cdr2p和Mdr1p的调节谱进行了总结，在此过程中发现了Cdr1p的选择性抑制剂。
本文描述了分子针对外排泵发挥活性的6种可能机制，并提供了文献中发现的近50种CaCdr1p调节剂及其各自机制（如果已确定）的列表，总结了目前在寻找可增强常用抗真菌药物效力的药物外排转运蛋白新抑制剂方面所取得的结果。还给出了列出的化合物针对Cdr1p、Cdr2p和Mdr1p的抑制谱表，最终指出了几种Cdr1p的选择性调节剂。
本综述的研究结果通过总结目前在这一健康科学新问题上取得的成果，有助于未来关于CaCdr1p及其调节剂的研究。需要对能够抑制Cdr1p的新型化合物进行进一步研究，以期完善本文提供的列表。
