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…
Diphenyl ether derivatives inhibit mycobacterial cell wall synthesis by inhibiting an enzyme, enoyl-acyl carrier protein reductase (InhA), which catalyses the last step in the fatty acid synthesis cycle of genus Mycobacterium. To select and validate a protein crystal structure of enoyl-acyl carrier protein reductase of Mycobacterium tuberculosis for designing inhibitors…
BACKGROUNDControl of the tuberculosis (TB) pandemic remains hindered in part by a lack of simple and accurate measures of treatment efficacy, as current gold standard markers rely on sputum-based assays that are slow and challenging to implement. However, previous work identified urinary N1, N12-diacetylspermine (DiAcSpm), neopterin, hydroxykynurenine, N-acetylhexosamine, ureidopropionic acid,…
