Characterization of Nocardithiocin Derivatives Produced by Amino Acid Substitution of Precursor Peptide notG

Abstract

Nocardithiocin is a thiopeptide compound produced by the pathogenic actinomycete Nocardia pseudobrasiliensis that displays activity against Gram-positive bacteria including drug-resistant Mycobacterium tuberculosis. However, the clinical use of nocardithiocin is hampered by light sensitivity and low water solubility. To improve these properties, the sixth amino acid of core peptide was substituted for other 19 amino acids by modifying the gene sequence of precursor peptide. Ten amino acids were successfully substituted to produce 1–3 novel compounds, of which six were the expected nocardithiocin derivatives. The compounds were tested for their stability, solubility, and antimicrobial activity. Of the 17 compounds produced, ten displayed antibiotic activity and two of them improved MIC value to bacteria. Furthermore, nocardithiocin and all derivatives were stable to the light. The substitution of amino acid sequence in precursor peptide could lead the successful production of nocardithiocin derivatives and alter its property. This report represents the first step of nocardithiocin utilization, and amino acid substitution technique can be used to create desirable nocardithiocin derivatives.