Convergent biosynthetic pathways to β-lactam antibiotics

Area of Science:

• Biochemistry
• Microbiology
• Medicinal Chemistry

Background:

• Beta-lactams are vital antimicrobial drugs, forming over 60% of human medicine's antimicrobial arsenal.
• Naturally occurring beta-lactams, derived from five families, have inspired these essential medicines.
• Their biosynthetic pathways exhibit diverse strategies converging on a common azetidinone ring structure.

Purpose of the Study:

• To explore the biosynthetic pathways of naturally occurring beta-lactams.
• To understand how these pathways generate the core azetidinone ring and modulate its reactivity.
• To investigate the evolutionary relationship between beta-lactam antibiotics and their target enzymes.

Main Methods:

• Analysis of known biosynthetic pathways for naturally occurring beta-lactams.
• Comparative analysis of enzyme mechanisms and active site geometries.
• Examination of structural features conferring selective binding and inhibition of d,d-transpeptidases.

Main Results:

• Biosynthetic pathways display highly individualized strategies for beta-lactam generation.
• A common azetidinone ring is assembled in specific structural contexts for enzyme inhibition.
• Beta-lactam antibiotics are kinetically competitive inhibitors of d,d-transpeptidases, crucial for bacterial peptidoglycan synthesis.
• Enzymes involved belong to a distinct clan of serine hydrolases, specifically targeted by beta-lactams.

Conclusions:

• Natural beta-lactam biosynthesis showcases remarkable enzymatic ingenuity and catalytic multitasking.
• The intrinsic reactivity of the beta-lactam core is modulated by ring strain and electronic effects in natural systems.
• Understanding these pathways provides insights into antibiotic evolution and the design of new antimicrobial agents.