Bacterial self-resistance to the natural proteasome inhibitor salinosporamide A.

Abstract

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 β-subunit, SalI, encoded within the salinosporamide biosynthetic gene cluster and biochemically characterized the SalI proteasome complex. The SalI β-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 SalI correlates to clinical bortezomib resistance from a human proteasome β5-subunit A49T mutation, suggesting that intrinsic resistance to natural proteasome inhibitors may predict clinical outcomes.

• Authors: Andrew J Kale, Ryan P McGlinchey, Anna Lechner, Bradley S Moore
• Journal: ACS chemical biology (ACS Chem Biol) Vol. 6 Issue 11 Pg. 1257-64 (Nov 18 2011) ISSN: 1554-8937 [Electronic] United States
• PMID: 21882868 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biological Products
• Boronic Acids
• Lactones
• Proteasome Inhibitors
• Protein Subunits
• Pyrazines
• Pyrroles
• Bortezomib
• marizomib
• Proteasome Endopeptidase Complex

Topics

• Actinobacteria (chemistry)
• Biological Products (chemistry, metabolism, pharmacology)
• Boronic Acids (pharmacology)
• Bortezomib
• Drug Resistance, Bacterial (drug effects)
• Humans
• Lactones (chemistry, metabolism, pharmacology)
• Models, Molecular
• Molecular Sequence Data
• Mutagenesis, Site-Directed
• Proteasome Endopeptidase Complex (genetics, isolation & purification)
• Proteasome Inhibitors
• Protein Subunits (antagonists & inhibitors, genetics)
• Pyrazines (pharmacology)
• Pyrroles (chemistry, metabolism, pharmacology)
• Substrate Specificity