Genome Mining Reveals the Phosphonoalamide Natural Products and a New Route in Phosphonic Acid Biosynthesis

Phosphonic acid natural products have potent inhibitory activities that have led to their application as antibiotics. Recent studies uncovered large collections of gene clusters encoding for unknown phosphonic acids across microbial genomes. However, our limited understanding of their metabolism presents a significant challenge toward accurately informing the discovery of new bioactive compounds directly from sequence information alone. Here, we use genome mining to identify a family of gene clusters encoding a conserved branch point unknown to bacterial phosphonic acid biosynthesis. The products of this gene cluster family are the phosphonoalamides, four new phosphonopeptides with l-phosphonoalanine as the common headgroup. Phosphonoalanine and phosphonoalamide A are antibacterials, with strongest inhibition observed against strains of Bacillus and Escherichia coli. Heterologous expression identified the gene required for transamination of phosphonopyruvate to phosphonoalanine, a new route for bacterial phosphonic acids encoded within genomes of diverse microbes. These results expand our knowledge of phosphonic acid diversity and pathways for their biosynthesis.