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

Publication ,  Journal Article
Polvi, EJ; Averette, AF; Lee, SC; Kim, T; Bahn, Y-S; Veri, AO; Robbins, N; Heitman, J; Cowen, LE
Published in: PLoS Genet
October 2016

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.

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Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

October 2016

Volume

12

Issue

10

Start / End Page

e1006350

Location

United States

Related Subject Headings

  • Signal Transduction
  • Protein Serine-Threonine Kinases
  • Pentetic Acid
  • Mutation
  • Morphogenesis
  • Mitogen-Activated Protein Kinases
  • Mice
  • Metals
  • Lipopeptides
  • Humans
 

Citation

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Polvi, E. J., Averette, A. F., Lee, S. C., Kim, T., Bahn, Y.-S., Veri, A. O., … Cowen, L. E. (2016). Metal Chelation as a Powerful Strategy to Probe Cellular Circuitry Governing Fungal Drug Resistance and Morphogenesis. PLoS Genet, 12(10), e1006350. https://doi.org/10.1371/journal.pgen.1006350
Polvi, Elizabeth J., Anna F. Averette, Soo Chan Lee, Taeyup Kim, Yong-Sun Bahn, Amanda O. Veri, Nicole Robbins, Joseph Heitman, and Leah E. Cowen. “Metal Chelation as a Powerful Strategy to Probe Cellular Circuitry Governing Fungal Drug Resistance and Morphogenesis.PLoS Genet 12, no. 10 (October 2016): e1006350. https://doi.org/10.1371/journal.pgen.1006350.
Polvi EJ, Averette AF, Lee SC, Kim T, Bahn Y-S, Veri AO, et al. Metal Chelation as a Powerful Strategy to Probe Cellular Circuitry Governing Fungal Drug Resistance and Morphogenesis. PLoS Genet. 2016 Oct;12(10):e1006350.
Polvi, Elizabeth J., et al. “Metal Chelation as a Powerful Strategy to Probe Cellular Circuitry Governing Fungal Drug Resistance and Morphogenesis.PLoS Genet, vol. 12, no. 10, Oct. 2016, p. e1006350. Pubmed, doi:10.1371/journal.pgen.1006350.
Polvi EJ, Averette AF, Lee SC, Kim T, Bahn Y-S, Veri AO, Robbins N, Heitman J, Cowen LE. Metal Chelation as a Powerful Strategy to Probe Cellular Circuitry Governing Fungal Drug Resistance and Morphogenesis. PLoS Genet. 2016 Oct;12(10):e1006350.

Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

October 2016

Volume

12

Issue

10

Start / End Page

e1006350

Location

United States

Related Subject Headings

  • Signal Transduction
  • Protein Serine-Threonine Kinases
  • Pentetic Acid
  • Mutation
  • Morphogenesis
  • Mitogen-Activated Protein Kinases
  • Mice
  • Metals
  • Lipopeptides
  • Humans