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Plant-derived antifungal agent poacic acid targets ?-1,3-glucan.

ABSTRACT: A rise in resistance to current antifungals necessitates strategies to identify alternative sources of effective fungicides. We report the discovery of poacic acid, a potent antifungal compound found in lignocellulosic hydrolysates of grasses. Chemical genomics using Saccharomyces cerevisiae showed that loss of cell wall synthesis and maintenance genes conferred increased sensitivity to poacic acid. Morphological analysis revealed that cells treated with poacic acid behaved similarly to cells treated with other cell wall-targeting drugs and mutants with deletions in genes involved in processes related to cell wall biogenesis. Poacic acid causes rapid cell lysis and is synergistic with caspofungin and fluconazole. The cellular target was identified; poacic acid localized to the cell wall and inhibited ?-1,3-glucan synthesis in vivo and in vitro, apparently by directly binding ?-1,3-glucan. Through its activity on the glucan layer, poacic acid inhibits growth of the fungi Sclerotinia sclerotiorum and Alternaria solani as well as the oomycete Phytophthora sojae. A single application of poacic acid to leaves infected with the broad-range fungal pathogen S. sclerotiorum substantially reduced lesion development. The discovery of poacic acid as a natural antifungal agent targeting ?-1,3-glucan highlights the potential side use of products generated in the processing of renewable biomass toward biofuels as a source of valuable bioactive compounds and further clarifies the nature and mechanism of fermentation inhibitors found in lignocellulosic hydrolysates.

SUBMITTER: Piotrowski JS

PROVIDER: S-EPMC4378397 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Plant-derived antifungal agent poacic acid targets β-1,3-glucan.

Piotrowski Jeff S JS Okada Hiroki H Lu Fachuang F Li Sheena C SC Hinchman Li L Ranjan Ashish A Smith Damon L DL Higbee Alan J AJ Ulbrich Arne A Coon Joshua J JJ Deshpande Raamesh R Bukhman Yury V YV McIlwain Sean S Ong Irene M IM Myers Chad L CL Boone Charles C Landick Robert R Ralph John J Kabbage Mehdi M Ohya Yoshikazu Y

Proceedings of the National Academy of Sciences of the United States of America 20150309 12

A rise in resistance to current antifungals necessitates strategies to identify alternative sources of effective fungicides. We report the discovery of poacic acid, a potent antifungal compound found in lignocellulosic hydrolysates of grasses. Chemical genomics using Saccharomyces cerevisiae showed that loss of cell wall synthesis and maintenance genes conferred increased sensitivity to poacic acid. Morphological analysis revealed that cells treated with poacic acid behaved similarly to cells tr ...[more]

PMID: 25775513

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Project description:Background(1,3)-?-D-Glucan has been widely used in clinical practice for the diagnosis of invasive Candida infections. However, such serum biomarker showed potential to guide antimicrobial therapy in order to reduce the duration of empirical antifungal treatment in critically ill septic patients with suspected invasive candidiasis.MethodsThis was a single-centre, randomized, open-label clinical trial in which critically ill patients were enrolled during the admission to the intensive care unit (ICU). All septic patients who presented invasive Candida infection risk factors and for whom an empirical antifungal therapy was commenced were randomly assigned (1:1) in those stopping antifungal therapy if (1,3)-?-D-glucan was negative ((1,3)-?-D-glucan group) or those continuing the antifungal therapy based on clinical rules (control group). Serum 1,3-?-D-glucan was measured at the enrolment and every 48/72?h over 14?days afterwards. The primary endpoint was the duration of antifungal treatment in the first 30?days after enrolment.ResultsWe randomized 108 patients into the (1,3)-?-D-glucan (n?=?53) and control (n?=?55) groups. Median [IQR] duration of antifungal treatment was 2?days [1-3] in the (1,3)-?-D-glucan group vs. 10?days [6-13] in the control group (between-group absolute difference in means, 6.29?days [95% CI 3.94-8.65], p?<?0.001). Thirty-day mortality was similar (28.3% [(1,3)-?-D-glucan group] vs. 27.3% [control group], p?=?0.92) as well as the overall rate of documented candidiasis (11.3% [(1,3)-?-D-glucan group] vs. 12.7% [control group], p?=?0.94), the length of mechanical ventilation (p?=?0.97) and ICU stay (p?=?0.23).ConclusionsIn critically ill septic patients admitted to the ICU at risk of invasive candidiasis, a (1,3)-?-D-glucan-guided strategy could reduce the duration of empirical antifungal therapy. However, the safety of this algorithm needs to be confirmed in future, multicentre clinical trial with a larger population.Trial registrationClinicalTrials.gov, NCT03117439 , retrospectively registered on 18 April 2017.

Dataset Information

Plant-derived antifungal agent poacic acid targets ?-1,3-glucan.

Publications

Plant-derived antifungal agent poacic acid targets β-1,3-glucan.

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