文献类型：期刊文献

英文题名：Hyper-Synergistic Antifungal Activity of Rapamycin and Peptide-Like Compounds against Candida albicans Orthogonally via Tor1 Kinase

作者：Tong, Yaojun[4,7,8];Zhang, Jingyu[1];Wang, Luoqiang[2,3];Wang, Qinqin[2];Huang, Huang[4];Chen, Xiangyin[1];Zhang, Qing[1];Li, Hantian[4];Sun, Nuo[5];Liu, Guang[1];Zhang, Buchang[3];Song, Fuhang[2];Alterovitz, Gil[6];Dai, Huanqin[4];Zhang, Lixin[1]

机构：[1]East China Univ Sci & Technol, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[2]Chinese Acad Sci, Inst Microbiol, Key Lab Pathogen Microbiol & Immunol, Beijing 100101, Peoples R China;[3]Anhui Univ, Hefei 230601, Peoples R China;[4]Chinese Acad Sci, Inst Microbiol, State Key Lab Mycol, Beijing 100101, Peoples R China;[5]Georgetown Univ, Dept Microbiol & Immunol, Med Ctr, Washington, DC 20057 USA;[6]US Dept Vet Affairs, Natl Artificial Intelligence Inst, Washington, DC 20420 USA;[7]Shanghai Jiao Tong Univ, State Key Lab Microbial Metab, Shanghai 200240, Peoples R China;[8]Shanghai Jiao Tong Univ, Sch Life Sci & Biotechnol, Shanghai 200240, Peoples R China

年份：2021

卷号：7

期号：10

起止页码：2826

外文期刊名：ACS INFECTIOUS DISEASES

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000707979000007)】；

基金：This work was supported by grants from the National Key Research and Development Program of China (2020YFA0907200 and 2020YFA0907800), the National Natural Science Foundation of China (21877038, 31430002, 31320103911, 21877124, 31720103901), Shanghai Rising-Star Program (20QA1402800), the Open Project Funding of the State Key Laboratory of Bioreactor Engineering, and the 111 Project (B18022). L.Z. was also partially supported by Shandong Taishan Scholar Program of China.

语种：英文

外文关键词：Candida albicans; multidrug resistance; rapamycin; drug combination; synergism; TOR kinase

摘要：Candida albicans is a life-threatening, opportunistic fungal pathogen with a high mortality rate, especially within the immunocompromised populations. Multidrug resistance combined with limited antifungal drugs even worsens the situation. Given the facts that the current drug discovery strategies fail to deliver sufficient antifungals for the emerging multidrug resistance, we urgently need to develop novel approaches. By systematically investigating what caused the different antifungal activity of rapamycin in RPMI 1640 and YPD, we discovered that peptide-like compounds can generate a hyper-synergistic antifungal effect with rapamycin on both azole-resistant and sensitive clinical C. albicans isolates. The minimum inhibitory concentration (MIC) of rapamycin reaches as low as 2.14 nM (2(-9) mu g/mL), distinguishing this drug combination as a hyper-synergism by having a fractional inhibitory concentration (FIC) index <= 0.05 from the traditional defined synergism with an FIC index < 0.5. Further studies reveal that this hyper-synergism orthogonally targets the protein Tor1 and affects the TOR signaling pathway in C. albicans, very likely without crosstalk to the stress response, Ras/cAMP/PKA, or calcineurin signaling pathways. These results lead to a novel strategy of controlling drug resistant C. albicans infection in the immunocompromised populations. Instead of prophylactically administering other antifungals with undesirable side-effects for extended durations, we now only need to coadminister some nontoxic peptide additives. The novel antifungal strategy approached in this study not only provides a new therapeutic method to control fungal infections in rapamycin-taking immunocompromised patients but also mitigates the immunosuppressive side-effects of rapamycin, repurposing rapamycin as an antifungal agent with wide applications.