Hsp90 governs dispersion and drug resistance of fungal biofilms.
Hsp90 governs dispersion and drug resistance of fungal biofilms.
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DOI：
10.1371/journal.ppat.1002257
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发表时间：
2011-09
期刊：
影响因子：
6.7
通讯作者：
Cowen LE
中科院分区：
文献类型：
--
作者：
Robbins N;Uppuluri P;Nett J;Rajendran R;Ramage G;Lopez-Ribot JL;Andes D;Cowen LE
真菌生物膜是人类死亡的主要原因，并且由于其固有的耐药性而对大多数治疗无效。这些由多种细胞类型组成的复杂群落在留置医疗器械上形成，它们的根除通常需要手术切除受感染的器械。在这里，我们暗示分子伴侣Hsp90是生物膜分散和耐药性的关键调节因子。我们之前已经确定，在主要的人类真菌病原体白色念珠菌中，Hsp90通过稳定蛋白磷酸酶钙调磷酸酶和MAPK Mkc1，使浮游条件下耐药性的出现和维持。Hsp90还通过抑制cAMP-PKA信号传导调节温度依赖性白色念珠菌的形态发生。在这里，我们证明了Hsp90的基因缺失减少了体外白色念珠菌生物膜的生长和成熟，并损害了生物膜细胞的扩散。此外，在体外损害Hsp90的功能会破坏白色念珠菌生物膜对最广泛使用的一类抗真菌药物氮唑的耐药性。在浮游而非生物膜条件下，Hsp90的缺失导致钙调磷酸酶和Mkc1的减少，这表明Hsp90在这些不同的细胞状态下通过不同的机制调节耐药性。Hsp90水平的降低导致基质葡聚糖水平的显著降低，为Hsp90调节生物膜抗唑提供了一个令人注目的机制。在大鼠静脉导管感染模型中，Hsp90功能的基因或药理学损伤使氟康唑在根除生物膜方面从无效变为高效。最后，抑制Hsp90降低了最致命的霉菌烟曲霉生物膜对最新一类抗真菌药物棘白菌素的耐药性。因此，我们建立了一种调节生物膜耐药和分散的新机制，并且靶向Hsp90为改善生物膜感染治疗的临床效果提供了急需的策略。白色念珠菌和烟曲霉是世界范围内最常见的真菌感染病原体。这两种真菌都可以在宿主组织和驻留的医疗器械上形成生物膜，这些生物膜对抗真菌治疗具有很高的抵抗力。在这里，我们暗示分子伴侣Hsp90是生物膜分散和耐药性的关键调节因子。Hsp90功能受损会减少体外白色念珠菌生物膜的形成，损害生物膜细胞的扩散，潜在地阻断它们作为感染宿主的能力。此外，在体外和导管相关性念珠菌病的哺乳动物模型中，Hsp90功能的损害使白色念珠菌生物膜对最广泛使用的一类抗真菌药物氮唑的耐药性消失。在浮游而非生物膜条件下，关键的耐药调节因子在Hsp90水平降低时被耗尽，这表明Hsp90在这些不同的细胞状态下通过不同的机制调节耐药。Hsp90的降低显著降低了基质葡聚糖的水平，葡聚糖是一种对白色念珠菌生物膜耐药性很重要的碳水化合物。抑制Hsp90也降低了烟曲霉生物膜对最新一类抗真菌药物棘白菌素的耐药性。因此，靶向Hsp90为治疗多种真菌引起的生物膜感染提供了一种有希望的策略。
Fungal biofilms are a major cause of human mortality and are recalcitrant to most treatments due to intrinsic drug resistance. These complex communities of multiple cell types form on indwelling medical devices and their eradication often requires surgical removal of infected devices. Here we implicate the molecular chaperone Hsp90 as a key regulator of biofilm dispersion and drug resistance. We previously established that in the leading human fungal pathogen, Candida albicans, Hsp90 enables the emergence and maintenance of drug resistance in planktonic conditions by stabilizing the protein phosphatase calcineurin and MAPK Mkc1. Hsp90 also regulates temperature-dependent C. albicans morphogenesis through repression of cAMP-PKA signalling. Here we demonstrate that genetic depletion of Hsp90 reduced C. albicans biofilm growth and maturation in vitro and impaired dispersal of biofilm cells. Further, compromising Hsp90 function in vitro abrogated resistance of C. albicans biofilms to the most widely deployed class of antifungal drugs, the azoles. Depletion of Hsp90 led to reduction of calcineurin and Mkc1 in planktonic but not biofilm conditions, suggesting that Hsp90 regulates drug resistance through different mechanisms in these distinct cellular states. Reduction of Hsp90 levels led to a marked decrease in matrix glucan levels, providing a compelling mechanism through which Hsp90 might regulate biofilm azole resistance. Impairment of Hsp90 function genetically or pharmacologically transformed fluconazole from ineffectual to highly effective in eradicating biofilms in a rat venous catheter infection model. Finally, inhibition of Hsp90 reduced resistance of biofilms of the most lethal mould, Aspergillus fumigatus, to the newest class of antifungals to reach the clinic, the echinocandins. Thus, we establish a novel mechanism regulating biofilm drug resistance and dispersion and that targeting Hsp90 provides a much-needed strategy for improving clinical outcome in the treatment of biofilm infections. Candida albicans and Aspergillus fumigatus are the most common causative agents of fungal infections worldwide. Both species can form biofilms on host tissues and indwelling medical devices that are highly resistant to antifungal treatment. Here we implicate the molecular chaperone Hsp90 as a key regulator of biofilm dispersion and drug resistance. Compromising Hsp90 function reduced biofilm formation of C. albicans in vitro and impaired dispersal of biofilm cells, potentially blocking their capacity to serve as reservoirs for infection. Further, compromise of Hsp90 function abrogated resistance of C. albicans biofilms to the most widely deployed class of antifungal, the azoles, both in vitro and in a mammalian model of catheter-associated candidiasis. Key drug resistance regulators were depleted upon reduction of Hsp90 levels in planktonic but not biofilm conditions, suggesting that Hsp90 regulates drug resistance through different mechanisms in these distinct cellular states. Reduction of Hsp90 markedly reduced levels of matrix glucan, a carbohydrate important for C. albicans biofilm drug resistance. Inhibition of Hsp90 also reduced resistance of A. fumigatus biofilms to the newest class of antifungal, the echinocandins. Thus, targeting Hsp90 provides a promising strategy for the treatment of biofilm infections caused by diverse fungal species.
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DOI：
10.1086/651200
发表时间：
2010-07-01
期刊：
The Journal of infectious diseases
影响因子：
--
作者：
Nett JE;Sanchez H;Cain MT;Andes DR
通讯作者：
Andes DR
影响因子：
4.9
作者：
Balashov, Sergey V.;Park, Steven;Perlin, David S.
通讯作者：
Perlin, David S.
影响因子：
3.1
作者：
Mukherjee, PK;Chandra, J;Ghannoum, MA
通讯作者：
Ghannoum, MA
影响因子：
6.7
作者：
LaFayette SL;Collins C;Zaas AK;Schell WA;Betancourt-Quiroz M;Gunatilaka AA;Perfect JR;Cowen LE
通讯作者：
Cowen LE
影响因子：
3.1
作者：
Andes, D;Nett, J;Pitula, A
通讯作者：
Pitula, A