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• W2528150422 endingPage "e1006350" @default.
• W2528150422 startingPage "e1006350" @default.
• W2528150422 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." @default.
• W2528150422 created "2016-10-14" @default.
• W2528150422 creator A5015096870 @default.
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• W2528150422 creator A5028449351 @default.
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• W2528150422 creator A5052159588 @default.
• W2528150422 creator A5083378250 @default.
• W2528150422 date "2016-10-03" @default.
• W2528150422 modified "2023-10-17" @default.
• W2528150422 title "Metal Chelation as a Powerful Strategy to Probe Cellular Circuitry Governing Fungal Drug Resistance and Morphogenesis" @default.
• W2528150422 cites W1503938960 @default.
• W2528150422 cites W1822251815 @default.
• W2528150422 cites W1863510689 @default.
• W2528150422 cites W1915738035 @default.
• W2528150422 cites W1929821956 @default.
• W2528150422 cites W1961089940 @default.
• W2528150422 cites W1964339096 @default.
• W2528150422 cites W1967864456 @default.
• W2528150422 cites W1968846907 @default.
• W2528150422 cites W1977002759 @default.
• W2528150422 cites W1982151856 @default.
• W2528150422 cites W1985155016 @default.
• W2528150422 cites W1985210060 @default.
• W2528150422 cites W1986481314 @default.
• W2528150422 cites W1988604934 @default.
• W2528150422 cites W1993727333 @default.
• W2528150422 cites W1993902553 @default.
• W2528150422 cites W1995380559 @default.
• W2528150422 cites W1996443660 @default.
• W2528150422 cites W1997437177 @default.
• W2528150422 cites W1999340863 @default.
• W2528150422 cites W2014741756 @default.
• W2528150422 cites W2015142707 @default.
• W2528150422 cites W2015285897 @default.
• W2528150422 cites W2016562927 @default.
• W2528150422 cites W2018213464 @default.
• W2528150422 cites W2018239620 @default.
• W2528150422 cites W2019892034 @default.
• W2528150422 cites W2021225422 @default.
• W2528150422 cites W2027546225 @default.
• W2528150422 cites W2030271109 @default.
• W2528150422 cites W2031431271 @default.
• W2528150422 cites W2032893561 @default.
• W2528150422 cites W2038204439 @default.
• W2528150422 cites W2041180147 @default.
• W2528150422 cites W2041611856 @default.
• W2528150422 cites W2045507047 @default.
• W2528150422 cites W2047668666 @default.
• W2528150422 cites W2048093614 @default.
• W2528150422 cites W2049219353 @default.
• W2528150422 cites W2055593282 @default.
• W2528150422 cites W2056868286 @default.
• W2528150422 cites W2060816398 @default.
• W2528150422 cites W2061492510 @default.
• W2528150422 cites W2067823655 @default.
• W2528150422 cites W2068006302 @default.
• W2528150422 cites W2069408563 @default.
• W2528150422 cites W2072133744 @default.
• W2528150422 cites W2074593070 @default.
• W2528150422 cites W2082568641 @default.
• W2528150422 cites W2083233467 @default.
• W2528150422 cites W2085708633 @default.
• W2528150422 cites W2086110261 @default.
• W2528150422 cites W2086823906 @default.
• W2528150422 cites W2087273774 @default.
• W2528150422 cites W2089830565 @default.
• W2528150422 cites W2092294469 @default.
• W2528150422 cites W2095902301 @default.
• W2528150422 cites W2097400162 @default.
• W2528150422 cites W2097997586 @default.
• W2528150422 cites W2100005543 @default.
• W2528150422 cites W2106031809 @default.
• W2528150422 cites W2106769310 @default.
• W2528150422 cites W2107794472 @default.
• W2528150422 cites W2109847770 @default.
• W2528150422 cites W2113427739 @default.
• W2528150422 cites W2113880496 @default.
• W2528150422 cites W2114409750 @default.
• W2528150422 cites W2118225722 @default.
• W2528150422 cites W2119401994 @default.
• W2528150422 cites W2122718120 @default.
• W2528150422 cites W2123494469 @default.
• W2528150422 cites W2127997803 @default.
• W2528150422 cites W2128003379 @default.
• W2528150422 cites W2131508520 @default.
• W2528150422 cites W2131821856 @default.
• W2528150422 cites W2132121507 @default.
• W2528150422 cites W2132215733 @default.
• W2528150422 cites W2133183053 @default.
• W2528150422 cites W2134152343 @default.
• W2528150422 cites W2135707527 @default.
• W2528150422 cites W2136932683 @default.
• W2528150422 cites W2139472183 @default.
• W2528150422 cites W2140712528 @default.

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