Inactivation of the <i>Burkholderia</i> Toxin Malleicyprol by Enzymatic Cyclopropanol Ring Opening

Pathogenic bacteria of the Burkholderia pseudomallei group cause life-threatening infections in humans and animals. Their virulence factors include malleicyprols bearing a reactive cyclopropanol moiety essential for toxicity. Inactivating this reactive motif, therefore, is a promising way to neutralize these toxins. Here, we identify a heme-dependent oxidoreductase (BurK) that cleaves the cyclopropanol warhead. Mutational analyses and in vivo radical capturing show that BurK catalyzes a radical ring opening to yield a propanone fragment. Characterizing BurK orthologs across various bacterial phyla suggests broader ecological roles of these unusual enzymes. Using a nematode model, we demonstrate that BurK-producing helper bacteria neutralize malleicyprols, significantly reducing toxicity and enhancing host survival. In addition to uncovering a novel biocatalyst, this work lays the foundation for antivirulence approaches using therapeutic microbes against antibiotic-resistant pathogens.