Bacteria are inherently social organisms whose actions should ideally be studied within an interactive ecological context. We show that the exchange and modification of natural products enables two unrelated bacteria to defend themselves against a common predator. Amoebal predation is a major cause of death in soil bacteria and thus it exerts a strong selective pressure to evolve defensive strategies. A systematic analysis of binary combinations of coisolated bacteria revealed strains that were individually susceptible to predation but together killed their predator. This cooperative defense relies on a Pseudomonas species producing syringafactin, a lipopeptide, which induces the production of peptidases in a Paenibacillus strain. These peptidases then degrade the innocuous syringafactin into compounds, which kill the predator. A combination of bioprospecting, coculture experiments, genome modification, and transcriptomics unravel this novel natural product-based defense strategy.
Microbially produced
3-acyltetramic acids display a diverse range
of biological activities. The pyreudiones are new members of this
class that were isolated from bacteria of the genus Pseudomonas. Here, we performed a structure–activity relationship study
and determined their mode of action. An efficient biomimetic synthesis
was developed to synthesize pyreudione A. Pyreudiones and synthetic
analogs thereof were tested for their amoebicidal, antibacterial,
antiproliferative, and cytotoxic activities. The length of the alkyl
side chain and the nature of the amino acid residues within the tetramic
acid moiety strongly affected activity, in particular against mycobacteria.
The mode of action was shown to correlate with the ability of pyreudiones
to act as protonophores. Removal of the acidic proton by methylation
of pyreudione A resulted in a loss of bioactivity.
Low-molecular-weight natural products from microbes are indispensable in the development of potent drugs. However, their biological roles within an ecological context often remain elusive. Here, we shed light on natural products from eukaryotic microorganisms that have the ability to transition from single cells to multicellular organisms: the social amoebae. These eukaryotes harbor a large number of polyketide biosynthetic genes in their genomes, yet virtually none of the corresponding products can be isolated or characterized. Using complementary molecular biology approaches, including CRISPR-Cas9, we generated polyketide synthase (
pks5
) inactivation and overproduction strains of the social amoeba
Dictyostelium discoideum
. Differential, untargeted metabolomics of wild-type versus mutant fruiting bodies allowed us to pinpoint candidate metabolites derived from the amoebal PKS5. Extrachromosomal expression of the respective gene led to the identification of a yellow polyunsaturated fatty acid. Analysis of the temporospatial production pattern of this compound in conjunction with detailed bioactivity studies revealed the polyketide to be a spore germination suppressor.
Competitive inhibition of dehydroquinate synthase from Pisum sativum is observed with phosphonate (Ia) (Ki = 0.8 μM) and anhydro phosphonate (IIb) (Ki = 296 μM) while (Ib) and (IIa) do not inhibit substrate binding to Pisum dehydroquinate synthase.
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