Browse
Submit Data
Databases
API
Help

Dataset Information

15 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Analysis of Approaches to Anti-tuberculosis Compounds.

ABSTRACT: Mycobacterium tuberculosis (Mtb) remains a deadly pathogen two decades after the announcement of tuberculosis (TB) as a global health emergency by the World Health Organization. Medicinal chemistry efforts to synthesize potential drugs to shorten TB treatments have not always been successful. Here, we analyze physiochemical properties of 39 TB drugs and 1271 synthetic compounds reported in 40 publications from 2006 to early 2020. We also propose a new TB space of physiochemical properties that may provide more appropriate guidelines for design of anti-TB drugs.

SUBMITTER: Motamen S

PROVIDER: S-EPMC7658936 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Analysis of Approaches to Anti-tuberculosis Compounds.

Motamen Sara S Quinn Ronald J RJ

ACS omega 20201027 44

<i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) remains a deadly pathogen two decades after the announcement of tuberculosis (TB) as a global health emergency by the World Health Organization. Medicinal chemistry efforts to synthesize potential drugs to shorten TB treatments have not always been successful. Here, we analyze physiochemical properties of 39 TB drugs and 1271 synthetic compounds reported in 40 publications from 2006 to early 2020. We also propose a new TB space of physiochemical pro ...[more]

PMID: 33195903

Similar Datasets

Mycobacterium tuberculosis microarray to screen anti-tuberculosis compounds

Project description:Feature reduction of microarray data from mycobacteria treated with a variety of various clinical and investigational drugs

2013-04-24 | GSE46212 | GEO

Mycobacterium tuberculosis microarray to screen anti-tuberculosis compounds

Project description:Feature reduction of microarray data from mycobacteria treated with a variety of various clinical and investigational drugs We are using feature reduction to demonstrate that subsets of biomarker genes representative of the whole genome are sufficient for MOA classification and deconvolution in a medium-throughput microfluidic format ultimately leading to a cost effective and rapid tool for routine antibacterial drug-discovery programs.

2013-04-24 | E-GEOD-46212 | biostudies-arrayexpress

Identification of Anti-tuberculosis Compounds From Aurone Analogs.

Project description:The emergence of multidrug-resistant Mycobacterium tuberculosis (Mtb) strains has made tuberculosis (TB) control more difficult. Aurone derivatives have demonstrated promising anti-bacterial activities, but their effects against Mtb have not been thoroughly determined. In this study, we aimed to develop anti-TB compounds from aurone analogs. We used a fluorescent protein tdTomato labeled Mtb CDC1551 strain to screen 146 synthesized aurone derivatives for effective anti-TB compounds. The 9504, 9505, 9501, 9510, AA2A, and AA8 aurones inhibited the growth of Mtb with minimal inhibitory concentrations of 6.25, 12.5, 25, 25, 25, and 50 μM, respectively. We also examined cytotoxicities of the six leads against the human liver cell line HepG2, the primate kidney cell line Vero and human monocyte THP-1 derived macrophages. Three of the aurone leads (9504, 9501, and 9510) showed low cytotoxic effects on all three cell lines and high Mtb inhibitory efficacy (selectivity index > 10). Aurone 9504, 9501, AA2A, or AA8 significantly reduced the Mtb load in the lungs of infected mice after a 12-days treatment. We determined that the aurone leads inhibit Mtb chorismate synthase, an essential enzyme for aromatic acid synthesis. Our studies demonstrate the promise of synthetic aurones as novel anti-TB therapeutics.

| S-EPMC7251074 | biostudies-literature

Insight Into Novel Anti-tuberculosis Vaccines by Using Immunoinformatics Approaches.

Project description:Tuberculosis (TB), an infectious disease, has been a leading cause of morbidity and mortality for decades. The causative agent of TB is the Mycobacterium tuberculosis (Mtb) which can infects various parts of the body, mainly the lungs in pulmonary TB cases. Mycobacterium bovis Bacillus Calmette-Guerin (BCG) is the only approved vaccine for TB, but its efficiency to combat pulmonary TB is limited. Multidrug-resistant (MDR) TB and extensive drug-resistant (XDR) TB requires the evolution of more potent vaccines. Therefore, this research aims to generate a universal TB subunit vaccine using advanced immunoinformatics techniques. In generating a novel multiepitope subunit vaccine, we selected the conserved and experimentally confirmed antigens Rv0058, Rv0101, and Rv3343. After a rigorous evaluation, the top candidates from predicted Helper T-lymphocytes (HTL), Cytotoxic T-lymphocytes (CTL), and B-cell epitopes were considered potential vaccine candidates. Immunogenicity was enhanced by the addition of an adjuvant to the ultimate construct of the vaccine. B-cell epitopes predictions guaranteed the eventual induction of a humoral response. Thereafter, dynamics simulations and molecular docking validated the vaccine-receptor complex's stability and high affinity for the immune receptor TLR-3. Also, immune simulations revealed the significantly elevated levels of immunoglobulins such as IgM, cytokines such as interleukin-2, helper T (Th) cells, and cytotoxic T-cell populations. These results agreed with the actual inflammatory response and showed rapid antigen clearance after manifold exposure. Finally, the E. coli K12 strain was confirmed via in-silico cloning for quality expression. Nevertheless, in vivo experiments should be performed to validate the safety of the proposed vaccine and its inherent ability to prevent TB infection.

| S-EPMC9201507 | biostudies-literature

Insights into bioinformatic approaches for repurposing compounds as anti-viral drugs.

Project description:BackgroundDrug repurposing is a cost-effective strategy to identify drugs with novel effects. We searched for drugs exhibiting inhibitory activity to Herpes Simplex virus 1 (HSV-1). Our strategy utilized gene expression data generated from HSV-1-infected cell cultures which was paired with drug effects on gene expression. Gene expression data from HSV-1 infected and uninfected neurons were analyzed using BaseSpace Correlation Engine (Illumina®). Based on the general Signature Reversing Principle (SRP), we hypothesized that the effects of candidate antiviral drugs on gene expression would be diametrically opposite (negatively correlated) to those effects induced by HSV-1 infection.ResultsWe initially identified compounds capable of inducing changes in gene expression opposite to those which were consequent to HSV-1 infection. The most promising negatively correlated drugs (Valproic acid, Vorinostat) did not significantly inhibit HSV-1 infection further in African green monkey kidney epithelial cells (Vero cells). Next, we tested Sulforaphane and Menadione which showed effects similar to those caused by viral infections (positively correlated). Intriguingly, Sulforaphane caused a modest but significant inhibition of HSV-1 infection in Vero cells (IC50 = 180.4 µM, p = 0.008), but exhibited toxicity when further explored in human neuronal progenitor cells (NPCs) derived from induced pluripotent stem cells.ConclusionsThese results reveal the limits of the commonly used SRP strategy when applied to the identification of novel antiviral drugs and highlight the necessity to refine the SRP strategy to increase its utility.

| S-EPMC8411619 | biostudies-literature

Preparation and Evaluation of Potent Pentafluorosulfanyl-Substituted Anti-Tuberculosis Compounds.

Project description:The global fight to stop tuberculosis (TB) remains a great challenge, particularly with the increase in drug-resistant strains and a lack of funding to support the development of new treatments. To bolster a precarious drug pipeline, we prepared a focused panel of eight pentafluorosulfanyl (SF5 ) compounds which were screened for their activity against Mycobacterium tuberculosis (Mtb) H37Rv in three different assay conditions and media. All eight compounds had sub-micromolar potency, and four displayed MICs <100?nm. Seven compounds were evaluated against non-replicating and mono-drug-resistant Mtb, and for their ability to inhibit Mtb within the macrophage. The greatest potency was observed against intracellular Mtb (MIC <10?nm for three compounds), which is often the most challenging to target. In general, the SF5 -bearing compounds were very similar to their CF3 counterparts, with the major differences observed being their in?vitro ADME properties. Two SF5 -bearing compounds were found to have greater protein binding than their corresponding CF3 counterparts, but were also less metabolized in human microsomes, resulting in longer half-lives.

| S-EPMC5603227 | biostudies-literature

Discovery of Novel Anti-prion Compounds Using In Silico and In Vitro Approaches.

Project description:Prion diseases are associated with the conformational conversion of the physiological form of cellular prion protein (PrP(C)) to the pathogenic form, PrP(Sc). Compounds that inhibit this process by blocking conversion to the PrP(Sc) could provide useful anti-prion therapies. However, no suitable drugs have been identified to date. To identify novel anti-prion compounds, we developed a combined structure- and ligand-based virtual screening system in silico. Virtual screening of a 700,000-compound database, followed by cluster analysis, identified 37 compounds with strong interactions with essential hotspot PrP residues identified in a previous study of PrP(C) interaction with a known anti-prion compound (GN8). These compounds were tested in vitro using a multimer detection system, cell-based assays, and surface plasmon resonance. Some compounds effectively reduced PrP(Sc) levels and one of these compounds also showed a high binding affinity for PrP(C). These results provide a promising starting point for the development of anti-prion compounds.

| S-EPMC4598813 | biostudies-literature

Imidazole-Thiosemicarbazide Derivatives as Potent Anti-Mycobacterium tuberculosis Compounds with Antibiofilm Activity.

Project description:Mycobacterium tuberculosis (Mtb) is an intracellular pathogenic bacterium and the causative agent of tuberculosis. This disease is one of the most ancient and deadliest bacterial infections, as it poses major health, social and economic challenges at a global level, primarily in low- and middle-income countries. The lack of an effective vaccine, the long and expensive drug therapy, and the rapid spread of drug-resistant strains of Mtb have led to the re-emergence of tuberculosis as a global pandemic. Here, we assessed the in vitro activity of new imidazole-thiosemicarbazide derivatives (ITDs) against Mtb infection and their effects on mycobacterial biofilm formation. Cytotoxicity studies of the new compounds in cell lines and human monocyte-derived macrophages (MDMs) were performed. The anti-Mtb activity of ITDs was evaluated by determining minimal inhibitory concentrations of resazurin, time-kill curves, bacterial intracellular growth and the effect on biofilm formation. Mutation frequency and whole-genome sequencing of mutants that were resistant to ITDs were performed. The antimycobacterial potential of ITDs with the ability to penetrate Mtb-infected human macrophages and significantly inhibit the intracellular growth of tubercle bacilli and suppress Mtb biofilm formation was observed.

| S-EPMC8700351 | biostudies-literature

Hydride-induced Meisenheimer complex formation reflects activity of nitro aromatic anti-tuberculosis compounds.

Project description:The formation efficiency of hydride-induced Meisenheimer complexes of nitroaromatic compounds is consistent with their anti-TB activities exemplied by MDL860 and benzothiazol N-oxide (BTO) analogs. Herein we report that nitro cyano phenoxybenzenes (MDL860 and analogs) reacted slowly and incompletely which reflected their moderate anti-TB activity, in contrast to the instantaneous reaction of BTO derivatives to quantitatively generate Meisenheimer complexes which corresponded to their enhanced anti-TB activity. These results were corroborated by mycobacterial and radiolabelling studies that confirmed inhibition of the DprE1 enzyme by BTO derivatives but not MDL860 analogs.

| S-EPMC8130608 | biostudies-literature

Preparation of alginate-chitosan-cyclodextrin micro- and nanoparticles loaded with anti-tuberculosis compounds.

Project description:This paper describes the synthesis and application of alginate-chitosan-cyclodextrin micro- and nanoparticulate systems loaded with isoniazid (INH) and isoconazole nitrate (ISN) as antimycobacterial compounds. Preparation and morphology of the obtained particles, as well as antimycobacterial activity data of the obtained systems are presented. Docking of isoconazole into the active site of enoyl-acyl carrier protein reductase (InhA) of Mycobacetrium tuberculosis was carried out in order to predict the binding affinity and non-covalent interactions stabilizing the InhA-isoconazole complex. To assess these interactions, frontier molecular orbital calculations were performed for the active site of InhA and isoconazole obtained from docking. Isoconazole was predicted to be an active inhibitor of InhA with the analysis of the molecular docking and electron density distribution. It has been detected that alginate-chitosan-cyclodextrin microparticulate systems loaded with INH and ISN are as effective as pure INH applied in higher dosages.

| S-EPMC5082317 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data