Alboflavusins (AFNs)
are a group of cyclohexapeptides with moderate
antibacterial and antitumor activities from Streptomyces alboflavus sp. 313. In vivo and in vitro studies proposed that AFNs are biosynthesized
by a nonribosomal peptide synthetase machinery, and the 6-Cl-L-Trp precursor is supplied by a tryptophan halogenase gene
located outside the afn gene cluster. Guided by the
structure–activity relationship knowledge about the AFN-like
cyclohexapeptides, two dimeric AFNs (di-AFNs) with regiospecific biaryl
linkages were designed and generated biotechnologically by expressing
the P450 gene hmtS or clpS in S. alboflavus wild-type and mutant strains. The di-AFNs
displayed much better antibacterial and antitumor activities than
their monomers as anticipated, exemplifying a rational strategy to
generate natural product congeners with improved bioactivities.