A novel antibiotic mechanism of L-cyclopropylalanine blocking the biosynthetic pathway of essential amino acid L-leucine

Abstract

The unusual amino acid L-cyclopropylalanine was isolated from the mushroom Amanita virgineoides after detection in an anti-fungal screening test. L-Cyclopropylalanine was found to exhibit broad-spectrum inhibition against fungi and bacteria. The anti-fungal activity was found to be abolished in the presence of the amino acid L-leucine, but not any other amino acids, indicating that L-cyclopropylalanine may block the biosynthesis of the essential amino acid L-leucine, thereby inhibiting fungal and bacteria growth. Further biochemical studies found L-cyclopropylalanine indeed inhibits α-isopropylmalate synthase (α-IMPS), the enzyme that catalyzes the rate-limiting step in the biosynthetic pathway of L-leucine. Inhibition of essential L-leucine synthesis in fungal and bacteria organisms, a pathway absent in host organisms such as humans, may represent a novel antibiotic mechanism to counter the ever-increasing problem of drug resistance to existing antibiotics.