Bacterial Self-Resistance to the Natural Proteasome Inhibitor Salinosporamide A

Proteasome inhibitors have recently emerged as a therapeutic strategy in cancer chemotherapy, but susceptibility to drug resistance limits their. efficacy. The marine actinobacterium Salinispora tropica produces salinosporamide A (NPI-0052, marizomib), a potent proteasome inhibitor and promising clinical agent in the treatment of multiple myeloma. Actinobacteria also possess 20S proteasome machinery, raising the question of self resistance We identified a redundant proteasome beta-subunit, SalI, encoded within the salinosporamide biosynthetic gene cluster and biochemically characterized the Sall proteasome complex. The SalI beta-subunit has an altered substrate specificity profile, 30-fold resistance to salinosporamide A, and cross resistance to the FDA approved proteasome inhibitor bortezomib. An A49V mutation in Sall correlates to clinical bortezomib resistance from a human proteasome beta 5-subunit A49T mutation, suggesting that intrinsic resistance to natural proteasome inhibitors may predict clinical outcomes.