Leucinostatin Y: A Peptaibiotic Produced by the Entomoparasitic Fungus <i>Purpureocillium lilacinum</i> 40-H-28

Momose, Isao; Onodera, Takefumi; Doi, Hiroyasu; Adachi, Hayamitsu; Iijima, Masatomi; Yamazaki, Yasuharu; Sawa, Ryûichi; Kubota, Yumiko; Igarashi, Masayuki; Kawada, Manabu

doi:10.1021/acs.jnatprod.8b00839

Cited by 21 publications

(23 citation statements)

References 33 publications

(59 reference statements)

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“…Momose et al showed that leucinostatin Y, having ac arboxylic acid instead of at erminal amine,w as far less active against bacteria, fungi, and cancer cells than leucinostatin A( 1a). [21] However, comprehensive structure-activity relationships (SAR) have not been reported, and pressing issues remain unanswered. Here we present the first comprehensive structure-activity relationship of leucinostatin derivatives,d etermine the structural imperatives for in vitro antiprotozoal activity,a nd optimize the selectivity of the molecules.…”

Section: Methodsmentioning

confidence: 99%

“…Replacement of the unsaturated acyl chain with acetyl resulted in a1 000-fold decrease of the affinity.I na ddition, alanine scanning revealed that only the replacement of Aib-2 was tolerated, whereas replacement of amino acids Aib-3, Leu-5 and AHMOD-8 reduced the activity by an order of magnitude.Momose et al showed that leucinostatin Y, having ac arboxylic acid instead of at erminal amine,w as far less active against bacteria, fungi, and cancer cells than leucinostatin A( 1a). [21] However, comprehensive structure-activity relationships (SAR) have not been reported, and pressing issues remain unanswered. Here we present the first comprehensive structure-activity relationship of leucinostatin derivatives,d etermine the structural imperatives for in vitro antiprotozoal activity,a nd optimize the selectivity of the molecules.…”

Section: Introductionmentioning

confidence: 99%

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Antiprotozoal Structure–Activity Relationships of Synthetic Leucinostatin Derivatives and Elucidation of their Mode of Action

et al. 2021

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Leucinostatin Ai soneo ft he most potent antiprotozoal compounds ever described, but little was knowno n structure-activity relationships (SAR). We used Trypanosoma brucei as ap rotozoal model organism to test synthetically modified derivatives,r esulting in simplified but equally active compounds 2 (ZHAWOC6025) and 4 (ZHAWOC6027), which were subsequently modified in all regions of the molecule to gain an in-depth SAR understanding.T he antiprotozoal SAR matched SAR in phospholipid liposomes, where membrane integrity,l eaking, and dynamics were studied. The mode of action is discussed based on as tructure-activity analysis of derivatives in efficacy,u ltrastructural studies in T. brucei, and artificial membrane models,m imicking membrane stability and membrane potential. The main site of antiprotozoal action of natural and synthetic leucinostatins lies in the destabilization of the inner mitochondrial membrane,a sd emonstrated by ultrastructural analysis,e lectron microscopya nd mitochondrial staining.L ong-time sublethal exposure of T. brucei (200 passages) and siRNAs creening of 12'000 mutants showed no signs of resistance development to the synthetic derivatives.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Antiprotozoal Structure–Activity Relationships of Synthetic Leucinostatin Derivatives and Elucidation of their Mode of Action

et al. 2021

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“…The HR-ESI-MS spectrum indicated a molecular formula of C 58 H 105 N 10 O 13 corresponding to a mass of 1149.7864 [M + H] + and 12 degrees of unsaturation. As compared to leucinostatin Y [12], it lacked two carbons, one hydrogen, and two oxygens, which was confirmed by 13 C-NMR and 1 H-NMR spectroscopy. The complete assignments of all carbons are listed in Figure 1, Figure 2, and Figure S1 (available in supplementary data).…”

Section: Isolation and Structure Elucidation Of Secondary Metabolitesmentioning

confidence: 74%

New Peptaibiotics and a Cyclodepsipeptide from Ijuhya vitellina: Isolation, Identification, Cytotoxic and Nematicidal Activities

et al. 2020

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Fungal associations with nematodes have attracted scientific attention because of the need to develop new biocontrol agents. In this context, Ijuhya vitellina, an antagonistic fungus previously isolated from the plant parasitic cyst nematode Heterodera filipjevi, was selected to carry out an in-depth metabolomic study for its active metabolites. Herein, three new nonapeptide peptaibols with leucinostatin based sequences were isolated and identified by 1, 2D NMR, and HR-ESI-MS-MS. The absolute configuration was assigned based on Marfay’s analysis and Mosher ester formation. The new leucinostatins manifested moderate nematicidal effect against the plant pathogenic nematode Pratylenchus penetrans with LD90 values ranging from 5 to 7 µg/mL. Furthermore, a cyclodepsipeptide, named arthrichitin D, with five amino acid residues attached to a 3-hydroxy-2,4-dimethylhexadeca-4,6-dienoic fatty acid chain was discovered and showed weak nematicidal effect against Caenorhabditis elegans. Chaetoglobosin B and its 19-O-acetyl derivative were also obtained as minor metabolites, and the activity of chaetoglobosin B on the actin cytoskeleton of mammalian cells was assessed.

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“…P. lilacinum is known for the production of seven congeners of leucinostatins: A, B, C, D, F, H and K (Wang et al 2016). Recently, a new peptaibiotic called leucinostatin Y was isolated from the culture broth of P. lilacinum (Momose et al 2019). In a previous independent study, we also determined leucinostatins H and K as the major compounds in the culture filtrate of P. lilacinum based on the NMR studies (Elsherbiny et al 2019).…”

Section: Discussionmentioning

confidence: 99%

Action mechanisms and biocontrol of Purpureocillium lilacinum against green mould caused by Penicillium digitatum in orange fruit

Elsherbiny

Taher

El-Aziz

et al. 2021

J of Applied Microbiology

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Aims: The present study evaluated, for the first time, the inhibitory effects of the filtrate of Purpureocillium lilacinum against Penicillium digitatum. Methods and Results: No direct contact between P. lilacinum and P. digitatum was observed during the dual culture test and the inhibition zone was 6Á1 mm. The filtrate of P. lilacinum completely inhibited P. digitatum growth and spore germination at the concentration of 64%. The filtrate increased the permeability of the cell membrane and the content of MDA in P. digitatum. The ergosterol content in P. digitatum was strongly inhibited at 32% by 81Á1%. The green mould incidence and severity in filtrate-treated fruit at 64% were 71Á7 and 80Á7% lower than in the control, respectively. The filtrate enhanced the activity of PAL, PPO and POD enzymes in orange fruit. The POD and PAL gene expression levels were significantly upregulated in the fruit treated with the filtrate. Conclusions: This study indicated that the antifungal mechanism of P. lilacinum filtrate against P. digitatum is mainly by the damage of the fungal cell membrane and its components. Significance and Impact of the Study: This work provides the pioneer evidence on the application of P. lilacinum filtrate as a novel biocontrol agent for orange green mould.

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Leucinostatin Y: A Peptaibiotic Produced by the Entomoparasitic Fungus Purpureocillium lilacinum 40-H-28

Cited by 21 publications

References 33 publications

Antiprotozoal Structure–Activity Relationships of Synthetic Leucinostatin Derivatives and Elucidation of their Mode of Action

Antiprotozoal Structure–Activity Relationships of Synthetic Leucinostatin Derivatives and Elucidation of their Mode of Action

New Peptaibiotics and a Cyclodepsipeptide from Ijuhya vitellina: Isolation, Identification, Cytotoxic and Nematicidal Activities

Action mechanisms and biocontrol of Purpureocillium lilacinum against green mould caused by Penicillium digitatum in orange fruit

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