Pretomanid
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB32571 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR3323720_1.fastq.gz | Fastqsanger.gz | |||
| ERR3323720_2.fastq.gz | Fastqsanger.gz | |||
| ERR3323730_1.fastq.gz | Fastqsanger.gz | |||
| ERR3323730_2.fastq.gz | Fastqsanger.gz | |||
| ERR3323721_1.fastq.gz | Fastqsanger.gz |
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Project description:The ability of Mycobacterium tuberculosis (Mtb) to adopt heterogeneous physiological states, underlies it’s success in evading the immune system and tolerating antibiotic killing. Drug tolerant phenotypes are a major reason why the tuberculosis (TB) mortality rate is so high, with over 1.8 million deaths annually. To develop new TB therapeutics that better treat the infection (faster and more completely), a systems-level approach is needed to reveal the complexity of network-based adaptations of Mtb. Here, we report the transcriptional response of Mtb to the drug pretomanid. We performed transcriptomic sequencing (RNA-seq) on Mtb bacilli at 4, 24, 72 h following exposure to the drug.
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Project description:Resistance to bedaquiline, linezolid and pretomanid in pretomanid trials
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Project description:Mycobacterium tuberculosis transcriptional response to Pretomanid
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Project description:We applied RNAseq (Nextseq) technology to study mechanism of action of nitro-containing heterocycle antitubercular JSF-2019, with des-nitro JSF-2026 as control. Briefly, mid-log phase (OD = 0.3) M. tuberculosis culture was treated by 10x MIC of each compound in biological quadruplicates followed by mRNA extraction and RNAseq analysis. We find that JSF-2019 and pretomanid as intracellular NO• donors exhibited distinct transcriptional patterns comparing to extracellular iNOS inducer such as DETA/NO, therefore it suggests distinguished mechanisms of action between intracellular vs. extracellular NO• donors. We also observed that JSF-2019 upregulated a subset of FAS-II genes similar to isoniazid, indicating JSF-2019 inhibits intracellular mycolic acid biosynthesis.
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Project description:Ancient and recent differences in the intrinsic susceptibility of Mycobacterium tuberculosis complex to pretomanid
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Project description:In past, resistance mechanisms have been identified by analysis of resistant isolates or defined mutants. Recently, high-throughput transposon mutagenesis coupled with sequencing (TraDIS-Xpress) is another approach proving useful for elucidating the roles of genes involved in the overall cellular response to a particular stress. In this study, we used TraDIS-Xpress to determine the role played by genes following exposure to colistin stress. Approximately 10^7 cells from the mutant library were inoculated into LB broth at a range of doubling concentrations of colistin ( 0.25 x MIC, 0.5 x MIC, 1 x MIC, 2 X MIC). Experiments were performed with no induction, or with induction using 0.2 or 1 mM of Isopropyl β-D-1-thiogalactopyranoside (IPTG). All experiments were performed in duplicate.
2022-06-09 | E-MTAB-11807 | biostudies-arrayexpress
Project description:Given the low treatment success rates of drug-resistant tuberculosis (TB), novel TB drugs are urgently needed. The landscape of TB treatment has changed considerably over the last decade with the approval of three new compounds: bedaquiline, delamanid and pretomanid. Of these, delamanid and pretomanid belong to the same class of drugs, the nitroimidazoles. In order to close the knowledge gap on how delamanid and pretomanid compare with each other, we summarize the main findings from preclinical research on these two compounds. We discuss the compound identification, mechanism of action, drug resistance, in vitro activity, in vivo pharmacokinetic profiles, and preclinical in vivo activity and efficacy. Although delamanid and pretomanid share many similarities, several differences could be identified. One finding of particular interest is that certain Mycobacterium tuberculosis isolates have been described that are resistant to either delamanid or pretomanid, but with preserved susceptibility to the other compound. This might imply that delamanid and pretomanid could replace one another in certain regimens. Regarding bactericidal activity, based on in vitro and preclinical in vivo activity, delamanid has lower MICs and higher mycobacterial load reductions at lower drug concentrations and doses compared with pretomanid. However, when comparing in vivo preclinical bactericidal activity at dose levels equivalent to currently approved clinical doses based on drug exposure, this difference in activity between the two compounds fades. However, it is important to interpret these comparative results with caution knowing the variability inherent in preclinical in vitro and in vivo models.
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Project description:A population pharmacokinetic (PopPK) model for pretomanid was developed using data from 14 studies in the pretomanid development program: six phase 1 studies, six phase 2 studies, and two phase 3 studies. The final analysis data set contained 17,725 observations from 1,054 subjects, including healthy subjects and subjects with drug-sensitive, multidrug-resistant, or extensively drug-resistant pulmonary tuberculosis dosed pretomanid in monotherapy or combination therapy for up to 6 months. Pretomanid pharmacokinetic behavior was described by a one-compartment model that at a given dose was linear in its absorption and clearance processes but where the rate of absorption and extent of bioavailability changed with dose. Clearance and volume of distribution scaled allometrically with weight. Apparent clearance in females was 18% less than in males. Among HIV-positive subjects, absent the effect of CYP3A4-inducing antiretrovirals, apparent clearance was 6% higher. Some effects of total bilirubin and albumin were found, but the impacts on exposure were small. Bioavailability in the fasted condition was about half that in the fed condition. Relative bioavailability decreased with increasing dose in the fasted condition, but not for doses of ≤200 mg in the fed condition. HIV-positive subjects taking efavirenz and lopinavir/ritonavir had exposures that were reduced by 46 and 17%, respectively. There was little evidence for noteworthy effects of regimen partners on pretomanid. Standard diagnostics indicated that the model described the voluminous, diverse data well, so that the model could be used to generate exposure metrics for exposure/response analyses to be reported elsewhere.
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