Tuberculosis (TB) kills more people than any other infectious disease. Challenges for developing better treatments include the complex pathology due to within-host immune dynamics, interpatient variability in disease severity and drug pharmacokinetics-pharmacodynamics (PK-PD), and the growing emergence of resistance. Model-informed drug development using quantitative and translational pharmacology has become increasingly…
Hollow fiber systems (HFSs) have been widely applied to study pharmacokinetic-pharmacodynamic (PK-PD) relationships in antibiotic research and development. The system comprises a bundle of high-density hollow capillary fibers that conduct a flow of medium with or without drug and an extra-capillary space (ECS) inoculated with the pathogen of interest. The…
Treatment of tuberculosis necessitates combination therapy. Therefore, development of new tuberculosis therapies should consider multidrug effects because specific combinations may improve or reduce treatment efficacy through synergistic or antagonistic drug interactions, respectively. The standard assay of drug interactions is a checkerboard assay, wherein the drug-dose combinations are well-sampled across broad…
Models of nonreplication help us understand the biology of persistent Mycobacterium tuberculosis. High throughput screening (HTS) against nonreplicating M. tuberculosis may lead to identification of tool compounds that affect pathways on which bacterial survival depends in such states and to development of drugs that can overcome phenotypic resistance to conventional…
Antimicrobial susceptibility testing is the mainstay of tuberculosis drug development programs. In this chapter, we describe methods for determination of the minimum inhibitory concentration of compounds against Mycobacterium tuberculosis growing in liquid media as a function of carbon source, detergent, and environmental stress imposed by acidic pH as well as…
: We characterized BCG isolates found in lung and brain samples from a previously vaccinated patient with IFNγR1 deficiency. The isolates collected displayed distinct genomic and phenotypic features consistent with host adaptation and associated changes in antibiotic susceptibility and virulence traits. : We report a case of a patient with…
Screening of a diversity-oriented compound library led to the identification of two 6,11-dioxobenzo[]pyrido[1,2-]indoles (DBPI) that displayed low micromolar bactericidal activity against the Erdman strain of . The activity of these hit compounds was limited to tubercle bacilli, including the nonreplicating form, and to . On hit expansion and investigation of…
