Structure-Guided Development of a Potent BioA Inhibitor Validates Biotin Synthesis Inhibition as a Therapeutic...

Area of Science:

• Medicinal Chemistry
• Microbiology
• Biochemistry

Background:

• Biotin biosynthesis is essential for bacterial survival.
• The enzyme aminotransferase BioA is a validated target for antimicrobial drug development.
• Existing inhibitors often lack potency or suitable pharmacokinetic properties.

Purpose of the Study:

• To develop a potent and selective inhibitor of bacterial BioA.
• To evaluate the efficacy of the inhibitor against Mycobacterium tuberculosis (Mtb) in vitro and in vivo.
• To establish targeting biotin biosynthesis as a therapeutic strategy for tuberculosis.

Main Methods:

• Structure-guided drug design and optimization of a screening hit.
• Biochemical assays to determine enzyme inhibition (Ki).
• Antimicrobial susceptibility testing (MIC) against Mtb and nontuberculous mycobacteria.
• In vitro studies on cell envelope stress and membrane remodeling.
• Pharmacokinetic profiling and in vivo efficacy studies in a low-biotin mouse model.

Main Results:

• Developed C48, a potent BioA inhibitor with a Ki of 200 pM.
• C48 demonstrated sub-micromolar MICs against Mtb and nontuberculous mycobacteria.
• In vitro studies showed C48 mimics biotin starvation by inducing cell envelope stress.
• Pharmacokinetic studies revealed excellent oral bioavailability and significantly improved drug exposure.
• In a relevant mouse model, C48 effectively reduced Mtb burden in lungs and spleen.

Conclusions:

• C48 is a highly potent and selective inhibitor of BioA with promising antimycobacterial activity.
• Targeting bacterial biotin biosynthesis is a viable therapeutic strategy for tuberculosis.
• C48 represents a potential new class of antibiotics against Mtb.