Targeting of Fumarate Hydratase from Mycobacterium tuberculosis Using Allosteric Inhibitors with a Dimeric-Binding...

Area of Science:

• Biochemistry
• Drug Discovery
• Microbiology

Background:

• Antibiotic-resistant tuberculosis (TB) poses a significant global health threat, necessitating novel therapeutic targets and treatment strategies.
• Fumarate hydratase (fumarase) in Mycobacterium tuberculosis (Mtb) is a critical metabolic enzyme and a potential drug target.
• Selectively inhibiting Mtb fumarase is challenging due to its high similarity to the human enzyme, particularly the conserved active site.

Purpose of the Study:

• To develop novel inhibitors of Mycobacterium tuberculosis fumarase with improved selectivity over the human homolog.
• To explore a nonconserved allosteric site as a strategy for achieving target selectivity.
• To identify potent anti-TB compounds through structure-activity relationship studies and in vitro screening.

Main Methods:

• High-throughput screening to identify initial hits targeting Mtb fumarase.
• Structure-activity relationship (SAR) studies to optimize lead compounds.
• Determination of structural biology data for the lead series.
• In vitro screening of derivative compounds against Mtb for minimum inhibitory concentrations.

Main Results:

• Identification of a lead series that binds to a nonconserved allosteric site on Mtb fumarase.
• Optimization of the lead series resulted in derivatives with sub-micromolar inhibitory activity.
• Screening of these derivatives against Mtb identified compounds with potent minimum inhibitory concentrations.

Conclusions:

• Targeting the allosteric site of Mycobacterium tuberculosis fumarase is a viable strategy for developing selective inhibitors.
• The identified compounds represent promising leads for the development of new anti-tuberculosis drugs.
• Further development of these compounds could address the unmet need for treatments against antibiotic-resistant TB.