Proteasome inhibition as a therapeutic target for the fungal pathogen Cryptococcus neoformans.
Proteasome inhibition as a therapeutic target for the fungal pathogen Cryptococcus neoformans.
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DOI：
10.1128/spectrum.01904-23
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发表时间：
2023-09-26
影响因子：
3.7
通讯作者：
Kronstad, James W.
中科院分区：
文献类型：
--
作者：
Caza, Melissa;Santos, Daniel Assis;Burden, Elizabeth;Brisland, Anna;Hu, Guanggan;Kronstad, James W.
目前治疗真菌疾病的治疗挑战需要新的方法和新的药物。一个有前途的策略涉及与不同作用机制的药物联合治疗，以增加杀真菌活性并限制导致耐药性的突变的影响。在这项研究中，我们评估了硼替佐米的抗真菌潜力，通过检查抑制蛋白酶体活性，细胞增殖和胶囊生产的新型隐球菌，真菌脑膜脑炎的病原体。用缺失突变体的集合进行化学遗传筛选，确定了与硼替佐米联合治疗的潜在可药用靶点。硼替佐米与氟胞嘧啶、氯丙嗪、巴夫洛霉素A1、硫酸铜或羟基脲的联合体外试验显示了抗念珠菌的抗真菌作用。新人类此外，在隐球菌病的小鼠吸入模型中，硼替佐米和氟胞嘧啶的联合治疗导致神经功能的改善和真菌复制和传播的减少，导致疾病进展的延迟。因此，这项研究强调了化学遗传筛选在确定新治疗方法方面的实用性以及蛋白酶体抑制的抗真菌潜力。人类的真菌性疾病很难治疗，显然需要额外的抗真菌药物、更好的诊断方法、有效的疫苗和新的方法来应对新出现的耐药性。真菌的控制具有挑战性，因为它们与哺乳动物宿主具有许多共同的生化功能，因此很难确定药物开发的真菌特异性靶标。一种方法是将现有的抗真菌药物与靶向常见细胞过程的药物结合使用，其水平（理想情况下）对宿主无毒。在这项研究中，我们通过检查临床批准的蛋白酶体抑制剂硼替佐米影响新生隐球菌增殖和毒力的潜力来探索这种方法。我们发现，硼替佐米与抗隐球菌药物氟胞嘧啶的组合提高了感染小鼠的存活率，从而证明了这种抗真菌治疗策略的潜力。
The current therapeutic challenges for treating fungal diseases demand new approaches and new drugs. A promising strategy involves combination therapy with agents of distinct mechanisms of action to increase fungicidal activity and limit the impact of mutations leading to resistance. In this study, we evaluated the antifungal potential of bortezomib by examining the inhibition of proteasome activity, cell proliferation, and capsule production by Cryptococcus neoformans, the causative agent of fungal meningoencephalitis. Chemical genetic screens with collections of deletion mutants identified potential druggable targets for combination therapy with bortezomib. In vitro assays of combinations of bortezomib with flucytosine, chlorpromazine, bafilomycin A1, copper sulfate, or hydroxyurea revealed antifungal effects against C. neoformans. Furthermore, combination treatment with bortezomib and flucytosine in a murine inhalation model of cryptococcosis resulted in the improvement of neurological functions and reduced fungal replication and dissemination, leading to a delay in disease progression. This study therefore highlights the utility of chemical genetic screens to identify new therapeutic approaches as well as the antifungal potential of proteasome inhibition. Fungal diseases of humans are difficult to treat, and there is a clear need for additional antifungal drugs, better diagnostics, effective vaccines, and new approaches to deal with emerging drug resistance. Fungi are challenging to control because they share many common biochemical functions with their mammalian hosts and it is therefore difficult to identify fungal-specific targets for drug development. One approach is to employ existing antifungal drugs in combination with agents that target common cellular processes at levels that are (ideally) not toxic for the host. We pursued this approach in this study by examining the potential of the clinically approved proteasome inhibitor bortezomib to influence the proliferation and virulence of Cryptococcus neoformans. We found that the combination of bortezomib with the anti-cryptococcal drug flucytosine improved the survival of infected mice, thus demonstrating the potential of this strategy for antifungal therapy.
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DOI：
10.1038/s41579-021-00511-0
发表时间：
2021-07
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
Iyer KR;Revie NM;Fu C;Robbins N;Cowen LE
通讯作者：
Cowen LE
影响因子：
3.4
作者：
Coelho C;Casadevall A
通讯作者：
Casadevall A
影响因子：
64.5
作者：
Brown JCS;Nelson J;VanderSluis B;Deshpande R;Butts A;Kagan S;Polacheck I;Krysan DJ;Myers CL;Madhani HD
通讯作者：
Madhani HD
影响因子：
5.4
作者：
Goranov, Alexi I.;Madhani, Hiten D.
通讯作者：
Madhani, Hiten D.
影响因子：
16.6
作者：
Bard JAM;Goodall EA;Greene ER;Jonsson E;Dong KC;Martin A
通讯作者：
Martin A