Squalamine: an aminosterol antibiotic from the shark.

Abstract

In recent years, a variety of low molecular weight antibiotics have been isolated from diverse animal species. These agents, which include peptides, lipids, and alkaloids, exhibit antibiotic activity against environmental microbes and are thought to play a role in innate immunity. We report here the discovery of a broad-spectrum steroidal antibiotic isolated from tissues of the dogfish shark Squalus acanthias. This water-soluble antibiotic, which we have named squalamine, exhibits potent bactericidal activity against both Gram-negative and Gram-positive bacteria. In addition, squalamine is fungicidal and induces osmotic lysis of protozoa. The chemical structure of the antibiotic 313-N-1-{N-[3-(4-aminobutyl)]-1,3-diaminopropane}-7a,24'-dihydroxy-Sacholestane 24-sulfate has been determined by fast atom bombardment mass spectroscopy and NMR. Squalamine is a cationic steroid characterized by a condensation of an anionic bile salt intermediate with spermidine. The discovery of squalamine in the shark implicates a steroid as a potential host-defense agent in vertebrates and provides insights into the chemical design of a family of broad-spectrum antibiotics.Animals must defend themselves against environmental microbes if they are to survive. Multiple mechanisms of host defense against microbes have been described such as the array of humoral and cellular responses of the classical vertebrate immune system and less-specific physical and chemical barriers. Over the past several years, an increasing number of low molecular weight antibiotic substances, believed to play a role in defense against environmental microbes, have been isolated from diverse species of animals. These molecules include peptides (1-3), lipids (4, 5), and alkaloids (6-8).In the course of our studies exploring the diversity of antibiotics from animal sources, we have surveyed tissues from a number of animal species (9, 10). We focused our search for antibiotic substances on the gastrointestinal tract of various animals after the recent discovery of peptide antibiotics in the gut of frogs (11), pigs (12, 13), mice (14), and humans (34). In the course of our survey, we discovered that stomach extracts of the shark Squalus acanthias exhibited potent antimicrobial activity, prompting efforts to purify and identify the responsible molecule.In this report we describe the isolation, structural determination, and characterization of a water-soluble cationic steroid from the shark that exhibits potent antimicrobial activity against fungi, protozoa, and both Gram-negative and Gram-positive bacteria. This molecule is shown to be an unusual adduct of spermidine with an anionic bile salt intermediate that, to our knowledge, is without precedent in vertebrates. We have named the aminosterol "squalamine," derived from the genus Squalus and its chemical structure as an amine. MATERIALS AND METHODSPurification of Squlamine. Squalus acanthias sharks were captured off the New England coast. The shark stomach tissue (400 g) was frozen immediately after dissectio...

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“…1B), an antimicrobial aminosterol originally discovered in 1993 in the dogfish shark, Squalus acanthias (14). This small molecule, now prepared synthetically (see SI Materials and Methods for details), has been found to have pharmacological activity in endothelial cells by inhibiting growth factor-dependent pathways and thus has emerged as a drug candidate for the treatment of cancer and macular degeneration (15,16).…”

Tratamento da forma neovascular de degeneração macular relacionada à idade com drogas antiangiogênicas

“…Uma dessas substâncias foi encontrada em extratos estomacais do tubarão da espécie Squalus acanthias, sendo denominada por este motivo squalamina (49) . A squalamina é um aminoesterol esteroidal de peso molecular de 628 Da, catiônica, solúvel em água, com potentes propriedades antimicrobianas (50) .…”

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“…One of these products is squalamine, an aminosterol derived from shark liver first reported for its significant antibiotic activity (Moore et al, 1993). Further studies revealed that, squalamine inhibited angiogenesis (angiogenesis is the fundamental process by which persistent, unregulated blood vessels are formed) and solid tumor growth and blocked the mitogen-induced proliferation and migration of endothelial cells, preventing tumor neovascularization (Sills et al, 1998).…”