Inhibitors of amino acids biosynthesis as antifungal agents

Liu

Journal of Pineal Research

et al. 2018

Human health, food safety, and agriculture have been threatened by oomycetic diseases caused by notorious pathogenic oomycetes. Chemical oomyceticides are the main approaches in control of pathogenic oomycetes. However, the overused chemical oomyceticides have resulted in serious environmental pollution and drug resistance. The eco-friendly bio-oomyceticides are required for sustainable development through screening synergistic drug combinations. In this study, Phytophthora nicotianae (P. nicotianae), as one of the most destructive oomycetic diseases in agriculture, was used as a model system to screen the novel bio-oomyceticides based on drug combination. The results showed that treatment of melatonin or ethylicin (IUPAC Name: 1-ethylsulfonylsulfanylethane) alone displayed similar phenotypes such as the inhibition of the hyphal growth, reduction of the cell viability, and suppression of the virulence of P. nicotianae. Importantly, melatonin and ethylicin shared the same targets of interfering with the amino acid metabolism, overexpressing apoptosis-inducing factor, and dysregulating the virulence-related genes. Furthermore, strong synergism against P. nicotianae was induced by combining melatonin with ethylicin. Under treatment of the combination of melatonin and ethylicin, the expression of genes associated with amino acid, the apoptosis-inducing factor, and the virulence-related genes was much more significantly dysregulated than that of single drug treatment. Thus, the tobacco black shank caused by P. nicotianae can be successfully controlled using the combination of melatonin and ethylicin. These observations suggest that the synergistic effect based on the combination of melatonin and ethylicin is an eco-friendly alternative for the control of the destructive oomycetic diseases.

Section: Resultsmentioning

confidence: 99%

Synergistic anti‐oomycete effect of melatonin with a biofungicide against oomycetic black shank disease

Liu

Journal of Pineal Research

et al. 2018

Journal of Peptide Science

“…After being concentrated under vacuum, the yellow residue was purified by flash chromatography, with hexane/ethyl acetate 7:2 v/v mixture as an eluent, to give 4 as a yellow oil (2.5 g, 50% yield). 1 The 96-well microtiter plates were also used for determination of in vitro growth inhibitory activity in YPD and YNB-based media.…”

Section: (S)-3-benzyloxycarbonyl-4-(o-acetyl-3hydroxy-2-oxopropyl)-mentioning

confidence: 99%

“…Several inhibitors of enzymes catalyzing particular steps of amino acid biosynthesis pathways exhibit antifungal properties . One of them is an antibiotic RI‐331 (5‐hydroxy‐4‐oxo‐ l ‐norvaline/2‐amino‐5‐hydroxy‐4‐oxopentanoic acid, HONV), produced by Streptomyces spp .…”

Section: Introductionmentioning

confidence: 99%

“…KEYWORDS antifungal agents, dipeptides, homoserine dehydrogenase, oligopeptide uptake 1 | INTRODUCTION Several inhibitors of enzymes catalyzing particular steps of amino acid biosynthesis pathways exhibit antifungal properties. 1 One of them is an antibiotic RI-331 (5-hydroxy-4-oxo-L-norvaline/2-amino-5-hydroxy-4-oxopentanoic acid, HONV), produced by Streptomyces spp. 2 This compound is active in vitro against several human pathogenic yeasts and the plant pathogen Cladosporium fulvus but has no effect against Aspergillus spp.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Antifungal dipeptides incorporating an inhibitor of homoserine dehydrogenase

Skwarecki

Schielmann

Martynow

et al. 2018

The antifungal activity of 5-hydroxy-4-oxo-L-norvaline (HONV), exhibited under conditions mimicking human serum, may be improved upon incorporation of this amino acid into a dipeptide structure. Several HONV-containing dipeptides inhibited growth of human pathogenic yeasts of the Candida genus in the RPMI-1640 medium, with minimal inhibitory concentration values in the 32 to 64 μg mL −1 range. This activity was not affected by multidrug resistance that is caused by overexpression of genes encoding drug efflux proteins. The mechanism of antifungal action of HONV dipeptides involved uptake by the oligopeptide transport system, subsequent intracellular cleavage by cytosolic peptidases, and inhibition of homoserine dehydrogenase by the released HONV. The relative transport rates determined the anticandidal activity of HONV dipeptides.

Current Opinion in Microbiology

“…A wide range of chemicals inhibit enzymatic activities involved in amino acid biosynthesis, as recently reviewed by Jastrzębowska and Gabriel [38]. Unfortunately, the compounds either have not thus far been tested, or have showed limited effect, in animal models.…”

Section: Perspectives For Drug Developmentmentioning

confidence: 99%

Amino acid biosynthetic routes as drug targets for pulmonary fungal pathogens: what is known and why do we need to know more?

Amich

Bignell

2016

Amongst 1.5 million fatal mycoses of humans occurring annually [1], the vast majority involve the human lung as the primary site of pathogenesis, and are derived from organisms which occupy environmental niches. On entry into the respiratory system pathogenic fungi must draw upon metabolic versatility for survival and proliferation as the mammalian lung is a nutritionally limiting environment. The nutritional stresses encountered have exposed vulnerabilities which have long been viewed as potential antifungal targets, since humans lack several of the metabolic pathways which fungi rely upon for pathogenic growth. However the ability of saprophytic fungi to proteolytically liberate amino acids from exogenous protein sources, and the differential availabilities of amino acids in diverse host niches have undermined confidence in amino acid metabolism as a target for selectively toxic antifungal therapies. Recent studies have reopened this debate by revealing a number of anabolic amino acid pathways in pathogenic fungi as being essential for viability per se. This review examines new knowledge on fungal amino acid metabolism in fungal pathogens of the human lung with a view to highlighting important new advances and gaps in understanding. TITLE Role of amino acid metabolism in fungal pathogenicityThroughout the kingdoms of life, amino acids are important building blocks of proteins and critical sources of macroelements such as nitrogen and sulphur which, if not acquired via intrinsic anabolic metabolism, must be sourced from extrinsic sources. Although fungi can biosynthesise all 20 of the proteinogenic amino acids the uptake of exogenous amino acids is significantly energetically preferable [2]. Accordingly, saprophytic fungal genomes harbour a multitude of protease and peptidase, and amino acid transporter encoding genes to ensure the liberation and uptake of amino acids from exogenous proteinaceous substrates.Amongst the hierarchy of preferred nitrogen sources the nitrogen-rich amino acids glutamine and arginine are dominant, but other amino acids can also be utilised when starvation threatens. Several wide domain regulatory mechanisms operate to ensure that starvation for nitrogen, carbon or amino acids is met with an appropriate metabolic response. In response to intracellular glutamine levels AreA-type GATA factors interact with other transcription factors specific for the biosynthesis of alternative nitrogen sources eg proline [3,4], while amino acid starvation increases translation of the transcriptional activator CpcA to generate a broad-acting cellular response governing amino acid biosynthesis and uptake [5]. Cellular levels of cysteine and methionine reflect intracellular sulphur content and modulate sulphur uptake via sulphur metabolite repression involving the positive-acting