Zidovudine-β-Lactam Pronucleoside Strategy for Selective Delivery into Gram-Negative Bacteria Triggered by...

Area of Science:

• Medicinal Chemistry
• Antimicrobial Resistance
• Drug Discovery

Background:

• Antibacterial resistance is a critical global health concern, necessitating novel therapeutic strategies.
• Multidrug-resistant Gram-negative pathogens frequently produce beta-lactamases, enzymes that inactivate essential beta-lactam antibiotics.
• Existing antibacterial options are increasingly compromised by widespread resistance mechanisms.

Purpose of the Study:

• To investigate a novel prodrug approach to overcome bacterial resistance.
• To design and synthesize prodrugs selectively activated by bacterial beta-lactamases within the periplasm.
• To evaluate the antibacterial activity and preliminary safety of these novel compounds.

Main Methods:

• Synthesis of ten novel prodrug analogues featuring a monobactam promoiety linked to zidovudine (AZT).
• Assessment of selective enzymatic activation by a panel of beta-lactamases.
• Evaluation of biological activity against laboratory strains and clinical isolates, including preliminary stability and toxicity studies.

Main Results:

• Successful synthesis of ten prodrug analogues (compounds 5a-h) through multi-step chemical processes.
• Demonstration of selective enzymatic activation by various beta-lactamases, confirming prodrug cleavage.
• Identification of lead compounds with promising activity against resistant bacterial strains, alongside initial stability and toxicity data.

Conclusions:

• The developed prodrugs represent a promising strategy for combating antibacterial resistance by exploiting bacterial enzymatic machinery.
• Selective activation within the bacterial periplasm offers a targeted approach to deliver active antibacterial agents.
• Further development and evaluation are warranted to advance these compounds towards clinical application.