Project description:This study uses microarray analyses to examine baseline gene expression profiles for Mycobacterium tuberculosis complex clinical isolates relative to reference strain CDC1551 during log phase growth in vitro in 7H9 broth. For this in vitro analyses, log-phase mycobacteria in starter cultures grown to mid-log from frozen stocks were inoculated into 7H9-OADC medium in 25-cm2 vented flasks at an OD of ~0.05 and grown without shaking for ~1 week to an OD of ~0.5-0.6.
Project description:Tuberculosis (TB) is still a major global health challenge, killing over 1.5 million people each year, and hence, there is a need to identify and develop novel treatments for Mycobacterium tuberculosis (M. tuberculosis). The prevalence of infections caused by nontuberculous mycobacteria (NTM) is also increasing and has overtaken TB cases in the United States and much of the developed world. Mycobacterium abscessus (M. abscessus) is one of the most frequently encountered NTM and is difficult to treat. We describe the use of drug-disease association using a semantic knowledge graph approach combined with machine learning models that has enabled the identification of several molecules for testing anti-mycobacterial activity. We established that niclosamide (M. tuberculosis IC90 2.95 μM; M. abscessus IC90 59.1 μM) and tribromsalan (M. tuberculosis IC90 76.92 μM; M. abscessus IC90 147.4 μM) inhibit M. tuberculosis and M. abscessus in vitro. To investigate the mode of action, we determined the transcriptional response of M. tuberculosis and M. abscessus to both compounds in axenic log phase, demonstrating a broad effect on gene expression that differed from known M. tuberculosis inhibitors. Both compounds elicited transcriptional responses indicative of respiratory pathway stress and the dysregulation of fatty acid metabolism. Further testing against drug-resistant isolates and other NTM is warranted to clarify the usefulness of these repurposed drugs for mycobacteria.
Project description:This study uses microarray analyses to examine baseline gene expression profiles for Mycobacterium tuberculosis complex clinical isolates relative to reference strain CDC1551 during log phase growth in vitro in 7H9 broth. For this in vitro analyses, log-phase mycobacteria in starter cultures grown to mid-log from frozen stocks were inoculated into 7H9-OADC medium in 25-cm2 vented flasks at an OD of ~0.05 and grown without shaking for ~1 week to an OD of ~0.5-0.6. Computed
Project description:In this study, we report the identification of a five-locus copper-inducible regulon in Mycobacterium tuberculosis. The identification of a copper responsive regulon unique to pathogenic Mycobacteria suggests copper homeostasis must be maintained during an infection.
