Discovery of nicoyamycin A, an inhibitor of uropathogenic <i>Escherichia coli</i> growth in low iron environments

Mike, Laura A.; Tripathi, Ashootosh; Blankenship, Connor; Saluk, Alyssa; Schultz, Pamela J.; Tamayo‐Castillo, Giselle; Sherman, David H.; Mobley, Harry L. T.

doi:10.1039/c7cc07732g

Cited by 6 publications

(17 citation statements)

References 39 publications

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“…Adipostatin E (10) was purified as light yellow amorphous solid possessing the molecular formula of C 22 H 38 O 2 based on [M+H] + ion peak m/z 335.2899 . The 1 H and 13 C NMR data, recorded in CD 3 OD, indicated the polyketidic nature of 10 with the tell-tale presence of 1 H NMR peak at δ 1.31 suggesting an aliphatic chain consisting primarily of methylene groups. The presence of triplet at δ H 0.86 (δ C 11.2) suggested a terminal methyl group, which in turn showed a COSY relay with δ H 1.32 (δ C 30.1) methylene connected to the tertiary carbon (δ C 40.3) through δ H 1.18.…”

Section: Isolation and Structural Elucidation Of The Adipostatins (6-7 10-15)mentioning

confidence: 98%

“…The extensive 1D and 2D NMR spectra revealed equivalent chemical shifts compared to the carbon skeleton of 10 and 11 with the only apparent difference appearing as an additional CH 2 component (Fig . Further characterization revealed a clear difference at the terminus of the aliphatic chain; where the presence of a clear doublet at δ h 0.90 (δ c 23.1) in 12 and a triplet at δ h 0.88 (δ c 22.7) in 13 established them to be adipostatins G ( 12) and H (13), respectively (Table I; Fig 4).…”

Section: Isolation and Structural Elucidation Of The Adipostatins (6-7 10-15)mentioning

confidence: 99%

“…A recurring bioactivity guided preparative C18 fractionation (Fig SI -7) and ensuing yielded two known adipostatins A-B (6)(7), which were also reported to be isolated from Streptomyces sp., 18 and six new congeners, adipostatins E-J (10)(11)(12)(13)(14)(15) with structures likely derived from a type I polyketide synthase pathway.…”

Section: Isolation and Structural Elucidation Of The Adipostatins (6-7 10-15)mentioning

confidence: 99%

“…Furthermore, the 13 C and HSQC NMR spectra revealed the presence of at least three quaternary carbons at δ C 145.3 (an aromatic carbon) and δ C 159.2 (two aromatic carbons). Moreover, the COSY correlations between two equivalent aromatic protons with signals at δ h 6.08, 6.12 along with their gHMBCAD correlation with carbons at δ c 100.9, 107.9, 145.3 and 159.2 unambiguously demonstrated the presence of a resorcinol moiety (Table I; Figure .…”

Section: Isolation and Structural Elucidation Of The Adipostatins (6-7 10-15)mentioning

confidence: 99%

“…In our ongoing quest to discover new structural classes of antibiotics, 5,[12][13][14] we developed an in vitro high throughput assay against bacterial PPCS to investigate our unique natural product extract (NPE) library in the search for new microbial inhibitors. 15 Herein, we describe the discovery of six new congeners belonging to the adipostatin class of metabolites, isolated and characterized through an HTS campaign.…”

Section: Introductionmentioning

confidence: 99%

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Adipostatins E-J, new potent antimicrobials identified as inhibitors of coenzyme-A biosynthesis

Gomez-Rodriguez

Schultz

Tamayo‐Castillo

et al. 2020

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Phosphopantetheine is a key structural element in biological acyl transfer reactions found embedded within coenzyme A (CoA). Phosphopantothenoylcysteine synthetase (PPCS) is responsible for installing a cysteamine group within phosphopantetheine. Therefore, it holds considerable potential as a drug target for developing new antimicrobials. In this study, we adapted a biochemical assay specific for bacterial PPCS to screen for inhibitors of CoA biosynthesis against a library of marine microbial derived natural product extracts (NPEs). Analysis of the NPE derived from Streptomyces blancoensis led to the isolation of novel antibiotics (10-12, and 14) from the adipostatin class of molecules. The most potent molecule (10) displayed in vitro activity with IC50= 0.93 μM, against S. pneumoniae PPCS. The whole cell antimicrobial assay against isolated molecules demonstrated their ability to penetrate bacterial cells and inhibit clinically relevant pathogenic strains. This establishes the validity of PPCS as a pertinent drug target, and the value of NPEs to provide new antibiotics

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Section: Isolation and Structural Elucidation Of The Adipostatins (6-7 10-15)mentioning

confidence: 98%

Section: Isolation and Structural Elucidation Of The Adipostatins (6-7 10-15)mentioning

confidence: 99%

Section: Isolation and Structural Elucidation Of The Adipostatins (6-7 10-15)mentioning

confidence: 99%

Section: Isolation and Structural Elucidation Of The Adipostatins (6-7 10-15)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Adipostatins E-J, new potent antimicrobials identified as inhibitors of coenzyme-A biosynthesis

Gomez-Rodriguez

Schultz

Tamayo‐Castillo

et al. 2020

Tetrahedron Letters

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Immobilized FhuD2 Siderophore-Binding Protein Enables Purification of Salmycin Sideromycins from Streptomyces violaceus DSM 8286

2018

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Siderophores are a structurally diverse class of natural products common to most bacteria and fungi as iron(III)-chelating ligands. Siderophores, including trihydroxamate ferrioxamines, are used clinically to treat iron overload diseases and show promising activity against many other iron-related human diseases. Here, we present a new method for the isolation of ferrioxamine siderophores from complex mixtures using affinity chromatography based on resin-immobilized FhuD2, a siderophore-binding protein (SBP) from Staphylococcus aureus. The SBP-resin enabled purification of charge positive, charge negative, and neutral ferrioxamine siderophores. Treatment of culture supernatants from Streptomyces violaceus DSM 8286 with SBP-resin provided an analytically pure sample of the salmycins, a mixture of structurally complex glycosylated sideromycins (siderophore-antibiotic conjugates) with potent antibacterial activity toward human pathogenic Staphylococcus aureus (minimum inhibitory concentration (MIC) = 7 nM). Siderophore affinity chromatography could enable the rapid discovery of new siderophore and sideromycin natural products from complex mixtures to aid drug discovery and metabolite identification efforts in a broad range of therapeutic areas.

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Expanding the Chemical Diversity of Secondary Metabolites Produced by Two Marine-Derived Enterocin- and Wailupemycin-Producing Streptomyces Strains

et al. 2023

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To expand the chemical diversity of secondary metabolites produced by two marine-derived enterocin-and wailupemycin-producing Streptomyces strains, OUCMDZ-3434 and OUCMDZ-2599, precursor feeding and solid fermentation strategies were used. Two new compounds, wailupemycins Q (1) and R (2), were isolated from the extracts of liquid and solid fermentation of OUCMDZ-3434. Furthermore, during the fermentation of OUCMDZ-3434, p-fluorobenzoic acid was added as the key biosynthetic precursor, which resulted in the isolation of eight new fluorinated enterocin and wailupemycin derivatives (3− 10) and 10 previously reported analogues (11−20). From the solid fermentation extract of OUCMDZ-2599, a new sulfur-containing compound thiotetromycin B (21) and its known analogue thiotetromycin (22) were identified. Moreover, the solid fermentation strategy effectively activated the biosynthesis of siderophores (23−25) of strain OUCMDZ-2599. Compound 3 showed moderate antibacterial activity against Staphylococcus aureus and methicillin-resistant Staphylococcus aureus subsp. aureus with MIC values of 4 μg/mL. Compounds 23−25 were significantly capable of binding Fe(III).

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Discovery of nicoyamycin A, an inhibitor of uropathogenic Escherichia coli growth in low iron environments

Cited by 6 publications

References 39 publications

Adipostatins E-J, new potent antimicrobials identified as inhibitors of coenzyme-A biosynthesis

Adipostatins E-J, new potent antimicrobials identified as inhibitors of coenzyme-A biosynthesis

Immobilized FhuD2 Siderophore-Binding Protein Enables Purification of Salmycin Sideromycins from Streptomyces violaceus DSM 8286

Expanding the Chemical Diversity of Secondary Metabolites Produced by Two Marine-Derived Enterocin- and Wailupemycin-Producing Streptomyces Strains

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