Roles for Stress Response and Cell Wall Biosynthesis Pathways in Caspofungin Tolerance in Cryptococcus neoformans.
Limited antifungal diversity and availability are growing problems for the treatment of fungal infections in the face of increasing drug resistance. The echinocandins, one of the newest classes of antifungal drugs, inhibit production of a crucial cell wall component. However, these compounds do not...
| Published in: | Genetics Vol. 213; no. 1; pp. 213 - 228 |
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| Main Authors: | , , , |
| Format: | Journal Article |
| Published: |
Oxford University Press / USA
Sep2019
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| Online Access: | View this record in EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=138471914&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 138471914 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00166731 GNT jtl: Genetics issn: 00166731 maglogo: N pubinfo: dt: Sep2019 vid: 213 iid: 1 pid: 622 pub: Oxford University Press / USA artinfo: ui: 138471914 10.1534/genetics.119.302290 138471914 ppf: 213 ppct: 15 formats: tig: atl: Roles for Stress Response and Cell Wall Biosynthesis Pathways in Caspofungin Tolerance in Cryptococcus neoformans. aug: au: Pianalto, Kaila M. Blake Billmyre, R. Telzrow, Calla L. Andrew Alspaugh, J. affil: Department of Medicine and Duke University School of Medicine, Durham, North Carolina 27710 sug: subj: Genetic Screening Cryptococcus Analysis Caspofungin Analysis Stress, Physiological Metabolism Cellular Structures Metabolism Drug Tolerance Evaluation Animal Studies Mutation Signal Transduction Polysaccharides Analysis Hydrolases Analysis Phenotype Evaluation ab: Limited antifungal diversity and availability are growing problems for the treatment of fungal infections in the face of increasing drug resistance. The echinocandins, one of the newest classes of antifungal drugs, inhibit production of a crucial cell wall component. However, these compounds do not effectively inhibit the growth of the opportunistic fungal pathogen Cryptococcus neoformans, despite potent inhibition of the target enzyme in vitro. Therefore, we performed a forward genetic screen to identify cellular processes that mediate the relative tolerance of this organism to the echinocandin drug caspofungin. Through these studies, we identified 14 genetic mutants that enhance caspofungin antifungal activity. Rather than directly affecting caspofungin antifungal activity, these mutations seem to prevent the activation of various stress-induced compensatory cellular processes. For example, the pfa4D mutant has defects in the palmitoylation and localization of many of its target proteins, including the Ras1 GTPase and the Chs3 chitin synthase, which are both required for caspofungin tolerance. Similarly, we have confirmed the link between caspofungin treatment and calcineurin signaling in this organism, but we suggest a deeper mechanism in which caspofungin tolerance is mediated by multiple pathways downstream of calcineurin function. In summary, we describe here several pathways in C. neoformans that contribute to the complex caspofungin tolerance phenotype in this organism. pubtype: Academic Journal doctype: Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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