Lamoth Frédéric, Alexander Barbara D, Juvvadi Praveen R, Steinbach William J
Division of Infectious Diseases and International Health, Department of Medicine, Duke University Medical Center, Durham, NC, USA Clinical Microbiology Laboratory, Department of Pathology, Duke University Medical Center, Durham, NC, USA Service of Infectious Diseases, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland Institute of Microbiology, Lausanne University Hospital, Lausanne, Switzerland
Division of Infectious Diseases and International Health, Department of Medicine, Duke University Medical Center, Durham, NC, USA Clinical Microbiology Laboratory, Department of Pathology, Duke University Medical Center, Durham, NC, USA.
J Antimicrob Chemother. 2015 May;70(5):1408-11. doi: 10.1093/jac/dku549. Epub 2015 Jan 3.
Invasive mould infections are associated with a high mortality rate and the emergence of MDR moulds is of particular concern. Calcineurin and its chaperone, the heat shock protein 90 (Hsp90), represent an important pathway for fungal virulence that can be targeted at different levels. We investigated the antifungal activity of compounds directly or indirectly targeting the Hsp90-calcineurin axis against different mould species.
The in vitro antifungal activity of the anticalcineurin drug FK506 (tacrolimus), the Hsp90 inhibitor geldanamycin, the lysine deacetylase inhibitor trichostatin A and the Hsp70 inhibitor pifithrin-μ was assessed by the standard broth dilution method against 62 clinical isolates of Aspergillus spp. and non-Aspergillus moulds (Mucoromycotina, Fusarium spp., Scedosporium spp., Purpureocillium/Paecilomyces spp. and Scopulariopsis spp.)
FK506 had variable antifungal activity against different Aspergillus spp. and was particularly active against Mucor spp. Geldanamycin had moderate antifungal activity against Fusarium spp. and Paecilomyces variotii. Importantly, trichostatin A had good activity against the triazole-resistant Aspergillus ustus and the amphotericin B-resistant Aspergillus terreus as well as the MDR Scedosporium prolificans. Moreover, trichostatin A exhibited synergistic interactions with caspofungin against A. ustus and with geldanamycin against Rhizopus spp. for which none of the other agents showed activity. Pifithrin-μ exhibited little antifungal activity.
Targeting the Hsp90-calcineurin axis at different levels resulted in distinct patterns of susceptibility among different fungal species. Lysine deacetylase inhibition may represent a promising novel antifungal strategy against emerging resistant moulds.
侵袭性霉菌感染与高死亡率相关，多重耐药霉菌的出现尤其令人担忧。钙调神经磷酸酶及其伴侣热休克蛋白90（Hsp90）是真菌毒力的重要途径，可在不同水平上作为靶点。我们研究了直接或间接靶向Hsp90-钙调神经磷酸酶轴的化合物对不同霉菌种类的抗真菌活性。
采用标准肉汤稀释法，评估抗钙调神经磷酸酶药物FK506（他克莫司）、Hsp90抑制剂格尔德霉素、赖氨酸脱乙酰酶抑制剂曲古抑菌素A和Hsp70抑制剂pifithrin-μ对62株曲霉属临床分离株及非曲霉属霉菌（毛霉目、镰刀菌属、赛多孢子菌属、拟青霉属/拟青霉属和帚霉属）的体外抗真菌活性。
FK506对不同曲霉属的抗真菌活性各异，对毛霉属尤其有效。格尔德霉素对镰刀菌属和变色拟青霉有中等抗真菌活性。重要的是，曲古抑菌素A对三唑耐药的ustus曲霉和两性霉素B耐药的土曲霉以及多重耐药的多育赛多孢子菌有良好活性。此外，曲古抑菌素A与卡泊芬净对ustus曲霉以及与格尔德霉素对根霉属表现出协同相互作用，而其他药物对这些菌株均无活性。Pifithrin-μ的抗真菌活性较弱。
在不同水平靶向Hsp90-钙调神经磷酸酶轴导致不同真菌种类有不同的药敏模式。赖氨酸脱乙酰酶抑制可能是针对新出现的耐药霉菌的一种有前景的新型抗真菌策略。
