Engineering an Artificial Myxopyronin Derivative with Enhanced Metabolic Stability via Mutasynthesis

Area of Science:

• Microbiology
• Medicinal Chemistry
• Drug Discovery

Background:

• Multidrug-resistant pathogens pose a significant global health threat.
• Existing antibiotic development faces limitations in novelty and pipeline.
• Myxopyronins, myxobacterial α-pyrone antibiotics, offer a novel mechanism by inhibiting RNA polymerase at a distinct site.

Purpose of the Study:

• To explore mutasynthesis for generating novel myxopyronin derivatives.
• To engineer a heterologous expression system for analog production.
• To develop optimized α-pyrone antibiotics to combat antimicrobial resistance.

Main Methods:

• Utilized a heterologous expression system in Myxococcus xanthus DK1622.
• Engineered two carrier protein domain mutants to facilitate mutasynthesis.
• Produced and characterized novel myxopyronin analogs, including a trifluoromethyl-modified derivative.

Main Results:

• Successfully generated structurally diverse myxopyronin analogs via mutasynthesis.
• A novel trifluoromethyl-modified analog, previously requiring total synthesis, was produced.
• This analog demonstrated potent antimicrobial activity against Mycobacterium tuberculosis and Gram-positive pathogens.
• The analog exhibited favorable in vitro ADMET properties.

Conclusions:

• Mutasynthesis is a viable strategy for producing novel α-pyrone antibiotic derivatives.
• The engineered system enables efficient generation of compounds with potential therapeutic value.
• Optimized α-pyrone antibiotics show promise in addressing the urgent need for new treatments against antimicrobial resistance.