Discovery of the Pendulisporaceae: An extremotolerant myxobacterial family with distinct sporulation behavior and prolific specialized metabolism

Myxococcota represents a small bacterial phylum comprising seven families, which have been shown to be exceptionally rich producers of pharmaceutically interesting natural products. Because of the challenging microbiology of most Myxococcota, their cultured biodiversity is scarcely explored. This study introduces a divergent myxobacterial family, called Pendulisporaceae, with distinct sporulation behavior. Strikingly, 90% of their biosynthetic gene clusters have not been assigned to their respective products and are distinct from published gene-cluster families. The encoded biosynthetic machineries exhibit unprecedented chemistry and enzymology, including the first prokaryotic non-ribosomal peptide synthetase acetylation domain and a triple hybrid nonribosomal peptide-polyketide-terpene pathway. Isolated novel products of the latter, alongside a sorangicin antibiotic derivative, exhibit potent inhibition of a human pathogenic coronavirus and multidrug-resistant Staphylococcus aureus. Through description of the four Pendulispora strains, we expand the publicly available myxobacterial gene-cluster families by a striking 9% and enable further studies on myxobacterial sporulation.