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Metal Chelation as a Powerful Strategy to Probe Cellular Circuitry Governing Fungal Drug Resistance and Morphogenesis.

dc.contributor.author Polvi, EJ
dc.contributor.author Averette, AF
dc.contributor.author Lee, SC
dc.contributor.author Kim, T
dc.contributor.author Bahn, YS
dc.contributor.author Veri, AO
dc.contributor.author Robbins, N
dc.contributor.author Heitman, Joseph
dc.contributor.author Cowen, LE
dc.coverage.spatial United States
dc.date.accessioned 2016-12-01T14:36:48Z
dc.date.issued 2016-10
dc.identifier http://www.ncbi.nlm.nih.gov/pubmed/27695031
dc.identifier PGENETICS-D-16-00375
dc.identifier.uri https://hdl.handle.net/10161/13050
dc.description.abstract Fungal pathogens have evolved diverse strategies to sense host-relevant cues and coordinate cellular responses, which enable virulence and drug resistance. Defining circuitry controlling these traits opens new opportunities for chemical diversity in therapeutics, as the cognate inhibitors are rarely explored by conventional screening approaches. This has great potential to address the pressing need for new therapeutic strategies for invasive fungal infections, which have a staggering impact on human health. To explore this approach, we focused on a leading human fungal pathogen, Candida albicans, and screened 1,280 pharmacologically active compounds to identify those that potentiate the activity of echinocandins, which are front-line therapeutics that target fungal cell wall synthesis. We identified 19 compounds that enhance activity of the echinocandin caspofungin against an echinocandin-resistant clinical isolate, with the broad-spectrum chelator DTPA demonstrating the greatest synergistic activity. We found that DTPA increases susceptibility to echinocandins via chelation of magnesium. Whole genome sequencing of mutants resistant to the combination of DTPA and caspofungin identified mutations in the histidine kinase gene NIK1 that confer resistance to the combination. Functional analyses demonstrated that DTPA activates the mitogen-activated protein kinase Hog1, and that NIK1 mutations block Hog1 activation in response to both caspofungin and DTPA. The combination has therapeutic relevance as DTPA enhanced the efficacy of caspofungin in a mouse model of echinocandin-resistant candidiasis. We found that DTPA not only reduces drug resistance but also modulates morphogenesis, a key virulence trait that is normally regulated by environmental cues. DTPA induced filamentation via depletion of zinc, in a manner that is contingent upon Ras1-PKA signaling, as well as the transcription factors Brg1 and Rob1. Thus, we establish a new mechanism by which metal chelation modulates morphogenetic circuitry and echinocandin resistance, and illuminate a novel facet to metal homeostasis at the host-pathogen interface, with broad therapeutic potential.
dc.language eng
dc.relation.ispartof PLoS Genet
dc.relation.isversionof 10.1371/journal.pgen.1006350
dc.title Metal Chelation as a Powerful Strategy to Probe Cellular Circuitry Governing Fungal Drug Resistance and Morphogenesis.
dc.type Journal article
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/27695031
pubs.begin-page e1006350
pubs.issue 10
pubs.organisational-group Basic Science Departments
pubs.organisational-group Clinical Science Departments
pubs.organisational-group Duke
pubs.organisational-group Duke Cancer Institute
pubs.organisational-group Institutes and Centers
pubs.organisational-group Medicine
pubs.organisational-group Medicine, Infectious Diseases
pubs.organisational-group Molecular Genetics and Microbiology
pubs.organisational-group Pharmacology & Cancer Biology
pubs.organisational-group School of Medicine
pubs.publication-status Published online
pubs.volume 12
dc.identifier.eissn 1553-7404


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