[New orally active penem antibiotic: Farom]

Area of Science:

• Medicinal Chemistry
• Microbiology
• Structural Biology

Background:

• Development of novel antibiotics is crucial to combat rising antimicrobial resistance.
• Penem antibiotics offer a broad spectrum of activity but can be susceptible to bacterial resistance mechanisms.
• Extended-spectrum beta-lactamases (ESBLs) are a significant challenge in treating bacterial infections.

Purpose of the Study:

• To design and characterize a novel, orally active penem antibiotic, faropenem (Farom).
• To elucidate the mechanism of faropenem's stability against ESBLs.
• To investigate the binding characteristics of faropenem with penicillin-binding protein 2 (PBP2).

Main Methods:

• Conformational analysis of penem derivatives for drug design.
• Molecular modeling to study enzyme-inhibitor interactions (Michaelis complex with ESBL, complex with PBP2).
• Total synthesis of faropenem from (R)-1,3-butanediol, involving 2+2 cycloaddition and functional group substitution.

Main Results:

• Faropenem demonstrated potent antibacterial activity against a wide range of bacteria, including ESBL producers.
• Molecular modeling revealed faropenem's stability mechanism against ESBLs and its specific affinity for Escherichia coli PBP2.
• An efficient synthetic route for faropenem was established.

Conclusions:

• Faropenem is a promising orally active penem antibiotic with broad-spectrum efficacy.
• Its structural features confer resistance to ESBL degradation and target bacterial PBP2 effectively.
• The developed synthetic pathway allows for the production of this important therapeutic agent.