Starter Unit Promiscuity of Dictyostelid Type III Polyketide Synthases Generates Diverse Acylphloroglucinols with Antimicrobial Activity

Abstract

Cavenderia subdiscoidea and Cavenderia ungulata are dictyostelid social amoebae found in northern Thailand. Genomic analysis identified two type III polyketide synthase genes, designated cspks and cupks. Heterologous expression of both genes in Aspergillus oryzae NSAR1 yielded a variety of acylphloroglucinols derived from different starter units. Among these were cavenderic acids A−E (1−5) and two related ester derivatives (6−7). Compounds 1 and 2 are reported here for the first time as natural products, whereas compounds 3−7 are new compounds. Structural analysis suggested that compounds 1−7 are biosynthetically derived from C4−C10 α,ω-dicarboxylic acid CoA thioesters, representing a putative and unprecedented starter-unit class for type III PKSs. Additionally, four known acylphloroglucinols (8−10 and 12) and one new derivative (11), derived from saturated and unsaturated fatty acid starter units, were identified. These findings demonstrate the broad starter-unit promiscuity of Cavenderia type III PKSs and their ability to generate structurally diverse acylphloroglucinols when expressed in a heterologous host. Compounds 1, 3−4, and 8−11 were evaluated for antimicrobial activity. Compound 8 (jambone C) exhibited the strongest antibacterial activity against several Gram-positive bacteria. Comparison of the tested compounds further suggested that terminal polar functional groups reduced antibacterial activity, providing preliminary structure−activity relationship insights for acylphloroglucinols.