An In Vitro Caseum Binding Assay that Predicts Drug Penetration in Tuberculosis Lesions

Journal of Visualized Experiments : JoVE
Jansy P SarathyVéronique Dartois

Abstract

The eradication of tuberculosis disease requires drug regimens that can penetrate the multiple layers of complex pulmonary lesions. Drug distribution in the caseous cores of cavities and lesions is especially crucial because they harbor subpopulations of drug-tolerant bacteria also commonly referred to as persisters. Existing methods for the measurement of drug penetration in tuberculosis lesions involve costly and time-consuming in vivo pharmacokinetic studies coupled to bioanalytical or imaging techniques. The in vitro measurement of drug binding to caseum macromolecules was proposed as an alternative to such techniques since this binding hinders the passive diffusion of drug molecules through caseum. Rapid equilibrium dialysis is a fast and reliable system for performing plasma protein and tissue binding studies. In this protocol, we used a rapid equilibrium dialysis (RED) device to measure drug binding to homogenates of caseum that is excised from the lesions and cavities of tuberculosis-infected rabbits. The protocol also describes how to generate a surrogate matrix from lipid loaded THP-1 macrophages to use in place of caseum. This caseum/surrogate binding assay is an important tool in tuberculosis drug discovery and can ...Continue Reading

Citations

Dec 6, 2017·Antimicrobial Agents and Chemotherapy·Jansy P SarathyVéronique A Dartois
Feb 12, 2020·Antimicrobial Agents and Chemotherapy·Martin GengenbacherVéronique Dartois
Jun 26, 2020·Science Translational Medicine·Sarah M SchraderCarl Nathan
Sep 10, 2020·Antimicrobial Agents and Chemotherapy·G L DrusanoArnold Louie
Jul 13, 2021·Antimicrobial Agents and Chemotherapy·Jacqueline P ErnestVéronique Dartois
Feb 1, 2018·Chemical Reviews·Tianao Yuan, Nicole S Sampson

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