Biotransformation of synthetic steroid drugs by gut and environmental bacteria shapes the activity within the host, persistence, and environmental fate of these widely used pharmaceuticals. However, the scope of bacterial transformations of synthetic steroids, the enzymes involved, and the role of microbial cooperative metabolism in these processes remain poorly understood. Here, we systematically investigated the biotransformation of 20 synthetic and 2 natural steroids, including clinically relevant estrogens, progestogens, corticosteroids, and prodrugs, across 8 intestinal and 4 environmental bacterial species. We identified more than 130 biotransformation products and found that the tested bacteria catalyzed diverse reactions including ester hydrolysis, oxidation-reduction chemistry, and steroid side-chain cleavage. Notably, the aerobic environmental bacterium Sphingobium herbicidovorans catalyzed desmolase-like steroid side-chain cleavage, a transformation not previously reported in aerobic bacteria. Combining homology searches, gain-of-function screening, and expression proteomics we identified six steroid-transforming enzymes in S. herbicidovorans. We further demonstrated that distinct bacterial species cooperatively metabolize synthetic steroids through interspecies metabolic cross-feeding, enabling sequential activation and metabolism of corticosteroids across microbial communities. Together, our findings uncover previously unrecognized bacterial enzymes and community-level interactions involved in synthetic steroid metabolism, directly linking metabolites, enzymes, and community interactions and establishing microbial biotransformation as an important determinant of steroid drug fate in host-associated and environmental ecosystems, where mechanistic resolution of bacterial steroid pathways is essential to predict metabolic interactions within and across microbial communities.
Beliaeva, M. A., Gross, M. W., Singh, A., Papagiannidis, D., Savitski, M., Zimmermann, M.
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