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Chemical synthesis of a homoserine-mutant of the antibacterial, head-to-tail cyclized protein AS-48 by ?-ketoacid-hydroxylamine (KAHA) ligation.

ABSTRACT: An antibacterial cyclic AS-48 protein was chemically synthesized by ?-ketoacid-hydroxylamine (KAHA) ligation. Initial challenges associated with the exceptionally hydrophobic segments arising from the amphiphilic nature of the protein were resolved by the development of bespoke reaction conditions for hydrophobic segments, using hexafluoroisopropanol (HFIP) as a co-solvent. The synthetic protein displays similar biological activity and properties to those of the native protein. To support the current understanding of its antibacterial mode of action, we demonstrate the ability of AS-48 to be incorporated into synthetic multilamellar vesicles (MLVs).

SUBMITTER: Rohrbacher F

PROVIDER: S-EPMC5434751 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Chemical synthesis of a homoserine-mutant of the antibacterial, head-to-tail cyclized protein AS-48 by α-ketoacid-hydroxylamine (KAHA) ligation.

Rohrbacher Florian F Zwicky André A Bode Jeffrey W JW

Chemical science 20170424 5

An antibacterial cyclic AS-48 protein was chemically synthesized by α-ketoacid-hydroxylamine (KAHA) ligation. Initial challenges associated with the exceptionally hydrophobic segments arising from the amphiphilic nature of the protein were resolved by the development of bespoke reaction conditions for hydrophobic segments, using hexafluoroisopropanol (HFIP) as a co-solvent. The synthetic protein displays similar biological activity and properties to those of the native protein. To support the cu ...[more]

PMID: 28580120

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Project description:Herein, we describe the antifungal evaluation of 43 bisamidine compounds, of which 26 are new, having the scaffold [Am]-[HetAr]-[linker]-[HetAr]-[Am], in which [Am] is a cyclic or acyclic amidine group, [linker] is a benzene, pyridine, pyrimidine, pyrazine ring, or an aliphatic chain of two to four carbon, and [HetAr] is a 5,6-bicyclic heterocycle such as indole, benzimidazole, imidazopyridine, benzofuran, or benzothiophene. In the head-to-head series the two [HetAr] units are oriented such that the 5-membered rings are connected through the linker, and in the head-to-tail series, one of the [HetAr] systems is connected through the 6-membered ring; additionally, in some of the head-to-tail compounds, the [linker] is omitted. Many of these compounds exhibited significant antifungal activity against Candida albicans, Candida krusei, Candida glabrata, Candida parapsilosis, and Cryptococcus neoformans (MIC ? 4 ?g/ml). The most potent compounds, for example, P10, P19 and P34, are comparable in antifungal activities to amphotericin B (MIC 0.125 ?g/ml). They exhibited rapid fungicidal activity (>3 log10 decrease in cfu/ml in 4h) at concentrations equivalent to 4× the MIC in time kill experiments. The bisamidines strongly inhibited DNA, RNA and cell wall biosynthesis in C. albicans in macromolecular synthesis assays. However, the half-maximal inhibitory concentration for DNA synthesis was approximately 30-fold lower than those for RNA and cell wall biosynthesis. Fluorescence microscopy of intact cells of C. albicans treated with a bisamidine exhibited enhanced fluorescence in the presence of DNA, demonstrating that the bisamidine was localized to the nucleus. The results of this study show that bisamidines are potent antifungal agents with rapid fungicidal activity, which is likely to be the result of their DNA-binding activity. Although it was difficult to obtain a broad-spectrum antifungal compound with low cytotoxicity, some of the compounds (e.g., P9, P14 and P43) exhibited favorable CC50 values against HeLa cells and maintained considerable antifungal activity.

Dataset Information

Chemical synthesis of a homoserine-mutant of the antibacterial, head-to-tail cyclized protein AS-48 by ?-ketoacid-hydroxylamine (KAHA) ligation.

Publications

Chemical synthesis of a homoserine-mutant of the antibacterial, head-to-tail cyclized protein AS-48 by α-ketoacid-hydroxylamine (KAHA) ligation.

Similar Datasets

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