Prediction of Drug Penetration in Tuberculosis Lesions

Area of Science:

• Pharmacology
• Infectious Diseases
• Medicinal Chemistry

Background:

• Antibiotic penetration into necrotic tuberculosis lesions (caseum) is variable and poorly understood.
• Caseum is a critical site for Mycobacterium tuberculosis infection.
• Factors influencing drug partitioning within caseum are unknown.

Purpose of the Study:

• To investigate the factors governing antibiotic diffusion into necrotic tuberculosis lesions.
• To develop predictive tools for optimizing drug properties for better caseum penetration.
• To identify molecular characteristics that enhance or impede drug diffusion into caseum.

Main Methods:

• Developed a caseum binding assay and a high-throughput assay using rapid equilibrium dialysis with a caseum surrogate.
• Utilized MALDI mass spectrometry imaging to analyze drug distribution in caseum.
• Profiled 279 compounds to identify physicochemical drivers of diffusion.
• Applied principle component analysis and modeling to derive an in silico predictive signature.

Main Results:

• Drug binding to caseum inversely correlated with passive diffusion.
• High lipophilicity and poor solubility were major drivers of caseum binding.
• Molecular shape descriptors (ring count, aromatic rings, sp(2) carbons, volume-to-surface ratio) influenced diffusion.
• An in silico signature combining 69 molecular descriptors predicted caseum binding.
• A simple rule of thumb related hydrophobicity and aromatic ring count to caseum binding.

Conclusions:

• Drug binding to caseum macromolecules limits passive diffusion, impacting tuberculosis treatment efficacy.
• Molecular properties, particularly lipophilicity and shape, are critical determinants of drug penetration into necrotic lesions.
• Developed predictive tools and a rule of thumb to guide the design of new anti-tuberculosis drugs with improved caseum partitioning.