Squalamine: an aminosterol antibiotic from the shark.
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 3 beta-N-1-(N-[3-(4-aminobutyl)]- 1,3-diaminopropane)-7 alpha,24 zeta-dihydroxy-5 alpha-cholestane 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.
Moore
K S
KS
Division of Human Genetics and Molecular Biology, University of Pennsylvania School of Medicine, Philadelphia 19104.
Wehrli
S
S
Roder
H
H
Rogers
M
M
Forrest
J N
JN
McCrimmon
D
D
Zasloff
M
M
D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000302:isolation & purification* / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects; D002176:Candida albicans / Q000187:drug effects; D002777:Cholestanols / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D004284:Dogfish; D004912:Erythrocytes / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects*; D006801:Humans; D008099:Liver / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D009130:Muscle, Smooth / Q000737:chemistry*; D009928:Organ Specificity; D010247:Paramecium / Q000187:drug effects; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013270:Stomach / Q000737:chemistry*
D000900:Anti-Bacterial Agents; D002777:Cholestanols; C079655:squalamine