Nanoenabling MbtI Inhibitors for Next-Generation Tuberculosis Therapy

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Tuberculosis Research

Background:

• Tuberculosis (TB) remains a global health challenge requiring novel therapeutic strategies.
• Targeting essential Mycobacterium tuberculosis (Mtb) enzymes absent in humans offers a path to selective drug development.
• Mycobacterium tuberculosis salicylate synthase (MbtI) is a validated target crucial for Mtb virulence.

Purpose of the Study:

• To design, synthesize, and evaluate novel 5-phenylfuran-2-carboxylic acid derivatives as MbtI inhibitors.
• To optimize lead compounds for enhanced antitubercular activity and favorable safety profiles.
• To investigate the potential of polymersomes for targeted delivery of antitubercular agents.

Main Methods:

• Structure-based drug design and synthesis of 5-phenylfuran-2-carboxylic acid derivatives.
• Enzyme inhibition assays to determine IC50 values against MbtI.
• In vitro antitubercular activity testing against M. bovis BCG.
• Encapsulation of optimized compounds into poly(2-methacryloyloxyethyl phosphorylcholine)-poly(2-(diisopropylamino)ethyl methacrylate) (PMPC-PDPA) polymersomes (POs).

Main Results:

• Several potent MbtI inhibitors with significant antitubercular activity were identified.
• Optimized compound 5-(3-cyano-5-isobutoxyphenyl)furan-2-carboxylic acid (1e) showed strong MbtI inhibition (IC50 = 11.2 μM) and in vitro activity (MIC99 = 32 μM).
• Esters of 1e were successfully loaded into PMPC-PDPA polymersomes and demonstrated reduced Mtb viability upon intracellular delivery.

Conclusions:

• Novel 5-phenylfuran-2-carboxylic acid derivatives are effective MbtI inhibitors with promising antitubercular properties.
• Polymersomes serve as an effective drug delivery system for targeting intracellular mycobacteria.
• This study lays the groundwork for developing MbtI-targeted therapies using polymersome-based drug delivery for tuberculosis.