Synthesis and characterization of a novel inhibitor of an aminoglycoside-inactivating enzyme.

Kirst, Herbert A.; Marconi, Gary G.; Counter, F. T.; Ensminger, P. W.; Jones, Noel D.; Chaney, Michael O.; Toth, John E.; Allen, Norris E.

doi:10.7164/antibiotics.35.1651

Cited by 32 publications

(13 citation statements)

References 9 publications

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“…For instance, the chemically synthesized 4-Br-7HT is a potent inhibitor of multidrug resistant Acinetobacter baumanni (Cao et al, 2018). However, 7HT is currently produced only chemically by persulphate oxidation of tropolone, but it requires further purification to separate it from the byproducts 5HT, and 3,7-and 4,7dyhydroxytropolones (Nozoe et al, 1953;Kirst et al, 1982). Thus, bacterial production of 7HT may serve as an alternative source of precursor with sufficient purity for subsequent generation of novel derivatives.…”

Section: Discussionmentioning

confidence: 99%

7‐hydroxytropolone is the main metabolite responsible for the fungal antagonism of Pseudomonas donghuensis strain SVBP6

Muzio

Agaras

Masi

et al. 2020

Environmental Microbiology

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Summary Pseudomonas donghuensis strain SVBP6, an isolate from an agricultural plot in Argentina, displays a broad‐spectrum and diffusible antifungal activity, which requires a functional gacS gene but could not be ascribed yet to known secondary metabolites typical of Pseudomonas biocontrol species. Here, we report that Tn5 mutagenesis allowed the identification of a gene cluster involved in both the fungal antagonism and the production of a soluble tropolonoid compound. The ethyl acetate extract from culture supernatant showed a dose‐dependent inhibitory effect against the phytopathogenic fungus Macrophomina phaseolina. The main compound present in the organic extract was identified by spectroscopic and X‐ray analyses as 7‐hydroxytropolone (7HT). Its structure and tautomerism was confirmed by preparing the two key derivatives 2,3‐dimethoxy‐ and 2,7‐dimethoxy‐tropone. 7HT, but not 2,3‐ or 2,7‐dimethoxy‐tropone, mimicked the fungal inhibitory activity of the ethyl acetate extract from culture supernatant. The activity of 7HT, as well as its production, was barely affected by the presence of up to 50 μM added iron (Fe+2). To summarize, P. donghuensis SVBP6 produces 7HT under the positive control of the Gac‐Rsm cascade and is the main active metabolite responsible for the broad‐spectrum inhibition of different phytopathogenic fungi.

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Section: Discussionmentioning

confidence: 99%

7‐hydroxytropolone is the main metabolite responsible for the fungal antagonism of Pseudomonas donghuensis strain SVBP6

Muzio

Agaras

Masi

et al. 2020

Environmental Microbiology

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“…34 The IC 50 value was not recorded, but at 100 µg/mL complete inhibition was observed, and close to 80% inhibition was seen for both compounds at 10 µg/mL. In addition, the compound was shown to work by competing with ATP for the enzyme.…”

Section: Metalloenzyme Inhibitionmentioning

confidence: 90%

The biology and synthesis of α-hydroxytropolones

et al. 2014

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α-Hydroxytropolones are a subclass of the troponoid family of natural products that are of high interest due to their broad biological activity and potential as treatment options for several diseases. Despite this promise, there have been scarce synthetic chemistry-driven optimization studies on the molecules. The following review highlights key developments in the biological studies conducted on α-hydroxytropolones to date, including the few synthetic chemistry-driven optimization studies. In addition, we provide an overview of the methods currently available to access these molecules. This review is intended to serve as a resource for those interested in biological activity of α-hydroxytropolones, and inspire the development of new synthetic methods and strategies that could aid in this pursuit.

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“…The antimicrobial activity of 7-HT has so far been attributed to two features of this low-molecular weight compound: i) it is proven to be an inhibitor of enzymes, namely it suppresses the activity of aminoglycoside-inactivating enzyme [68] and inositol monophosphatase [69]; or ii) it acts as an iron chelator which possibly gives advantage to 7-HT producers in iron-deficient environments [20]. Our previous study showed that 7-HT contributes to the antibacterial effect of P482 against the selected strains of the Dickeya and Pectobacterium genera [10] under highly nutritional conditions such as LBagar or Tryptic Soy agar, since the 7-hydroxytropolone mutants (KN4705, KN4706 and KN4709) lost their antibacterial activity.…”

Section: Siderophore Biosynthesis As An Important But Not the Only Pamentioning

confidence: 99%

Necessity requires no decision: carbon source-dependent pattern of antimicrobial activity and gene expression in Pseudomonas donghuensis P482

Matuszewska

Maciag

Rajewska

et al. 2021

Preprint

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Pseudomonas donghuensis P482 is a tomato rhizosphere isolate with the ability to inhibit growth of bacterial and fungal plant pathogens. Herein, we analysed the impact of the carbon source on the antibacterial activity of P482 and expression of the selected genes of three genomic regions in the P482 genome. These regions are involved in the synthesis of pyoverdine, 7‑hydroxytropolone (7-HT) and an unknown compound (“cluster 17”) and are responsible for antimicrobial activity of P482. We showed that the P482 mutants, defective in these regions, show variations and contrasting patterns of growth inhibition of the target pathogen under given nutritional conditions (with glucose or glycerol as a carbon source). We also selected and validated the reference genes for gene expression studies in P. donghuensis P482. Amongst ten candidate genes, we found gyrB, rpoD and mrdA the most stably expressed. Using selected reference genes in RT-qPCR, we assessed the expression of the genes of interest under minimal medium conditions with glucose or glycerol as carbon sources. Glycerol was shown to negatively affect the expression of genes necessary for 7-HT synthesis. The significance of this finding in the light of the role of nutrient (carbon) availability in biological plant protection is discussed.

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Synthesis and characterization of a novel inhibitor of an aminoglycoside-inactivating enzyme.

Abstract: A novel low-molecular weight inhibitor of an aminoglycoside-inactivating enzyme, initially THE JOURNAL OF ANTIBIOTICS

Cited by 32 publications

References 9 publications

7‐hydroxytropolone is the main metabolite responsible for the fungal antagonism of Pseudomonas donghuensis strain SVBP6

7‐hydroxytropolone is the main metabolite responsible for the fungal antagonism of Pseudomonas donghuensis strain SVBP6

The biology and synthesis of α-hydroxytropolones

Necessity requires no decision: carbon source-dependent pattern of antimicrobial activity and gene expression in Pseudomonas donghuensis P482

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