Breakpoints #92 – Antibiotic Alchemy: Metallo-Beta-Lactamases
Feb 2, 2024
Delving into the world of metallo-beta-lactamases, the podcast explores novel beta lactams, inhibitors, and their uses for MBLs. The discussion is packed with nerdy pub trivia and essential details on combatting gram-negative resistance. Global spread of metallo-beta-lactamases, next-gen inhibitors, and complex treatment challenges post liver transplant are also discussed.
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Why MBLs Are Mechanically Distinct
- Metallo-β-lactamases (MBLs) are class B enzymes that use zinc in their active site to hydrolyze most β-lactams.
- B1 subclass (NDM, VIM, IMP) drives most clinical problems and is often plasmid-encoded, enabling rapid spread.
Huge Variant Diversity Changes Activity
- MBL variants differ in activity and many variants exist, altering hydrolysis profiles and clinical impact.
- Genome mining shows thousands of MBL-like sequences; only a fraction are characterized, so unknown threats likely exist.
Why MBL Inhibitors Are Hard To Make
- Inhibitor design must match MBL mechanism: options include binding/removing metal, displacing catalytic water, or mimicking reaction intermediates.
- These strategies explain why MBL inhibitors took longer to develop than serine-BLIs.