scholarly journals Metabolic fate of human immunoactive sterols in Mycobacterium tuberculosis

2020 ◽  
Author(s):  
Tatsiana Varaksa ◽  
Sergey Bukhdruker ◽  
Irina Grabovec ◽  
Egor Marin ◽  
Anton Kavaleuski ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Causes Of Death ◽  
Adaptive Immune ◽  
Resistant Strains ◽  
Human Immunity ◽  
Bioinformatics Study ◽  
Human Immune ◽  
A Site ◽  
Drug Resistant Strains ◽  
Oxidative Attack

AbstractMycobacterium tuberculosis (Mtb) infection is among top ten causes of death worldwide, and the number of drug-resistant strains is increasing. The direct interception of human immune signaling molecules by Mtb remains elusive, limiting drug discovery. Oxysterols and secosteroids regulate both innate and adaptive immune responses. Here we report a functional, structural, and bioinformatics study of Mtb enzymes initiating cholesterol catabolism and demonstrated their interrelation with human immunity. We show that these enzymes metabolize human immune oxysterol messengers. Rv2266 – the most potent among them – can also metabolize vitamin D3 (VD3) derivatives. High-resolution structures show common patterns of sterols binding and reveal a site for oxidative attack during catalysis. Finally, we designed a compound that binds and inhibits three studied proteins. The compound shows activity against Mtb H37Rv residing in macrophages. Our findings contribute to molecular understanding of suppression of immunity and suggest that Mtb has its own transformation system resembling the human phase I drug-metabolizing system.

Evaluation of efflux pump gene expression among drug susceptible and drug resistant strains of Mycobacterium tuberculosis from Iran

2015 ◽  
Vol 36 ◽  
pp. 23-26 ◽  
Author(s):  
Jalil Kardan Yamchi ◽  
Mehri Haeili ◽  
Seifu Gizaw Feyisa ◽  
Hossein Kazemian ◽  
Abdolrazagh Hashemi Shahraki ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mycobacterium Tuberculosis ◽  
Efflux Pump ◽  
Drug Resistant ◽  
Resistant Strains ◽  
Drug Resistant Strains

Mycobacterium tuberculosis topoisomerases and EthR as the targets for new anti-TB drugs development

2019 ◽  
Vol 11 (16) ◽  
pp. 2193-2203
Author(s):  
Rafal Sawicki ◽  
Grazyna Ginalska
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Short Review ◽  
Drug Resistant ◽  
Dna Topoisomerases ◽  
Antituberculosis Drugs ◽  
Drug Candidates ◽  
Computational Sciences ◽  
Resistant Strains ◽  
Drug Resistant Strains ◽  
New Strategies

The significant increase in the detection of drug-resistant strains of Mycobacterium tuberculosis caused an urgent need for the discovery new antituberculosis drugs. Development of bioinformatics and computational sciences enabled the progress of new strategies leading to design, discovery and identification of a series of interesting drug candidates. In this short review, we would like to present recently discovered compounds targeting important mycobacterial proteins: DNA topoisomerases and the transcriptional repressor of EthA monooxygenase – EthR.

scholarly journals The Immune System as Drug Target

2013 ◽  
Vol 5 ◽  
pp. III.S12145
Author(s):  
Darren R. Flower
Keyword(s):  
Immune System ◽  
Drug Targets ◽  
Adaptive Immune System ◽  
Therapeutic Interventions ◽  
Human Immune System ◽  
Adaptive Immune ◽  
Histocompatibility Complex ◽  
Human Immunity ◽  
Human Immune ◽  
Adaptive Immune Systems

The immune system is perhaps the largest yet most diffuse and distributed somatic system in vertebrates. It plays vital roles in fighting infection and in the homeostatic control of chronic disease. As such, the immune system in both pathological and healthy states is a prime target for therapeutic interventions by drugs–-both small-molecule and biologic. Comprising both the innate and adaptive immune systems, human immunity is awash with potential unexploited molecular targets. Key examples include the pattern recognition receptors of the innate immune system and the major histocompatibility complex of the adaptive immune system. Moreover, the immune system is also the source of many current and, hopefully, future drugs, of which the prime example is the monoclonal antibody, the most exciting and profitable type of present-day drug moiety. This brief review explores the identity and synergies of the hierarchy of drug targets represented by the human immune system, with particular emphasis on the emerging paradigm of systems pharmacology.

scholarly journals In Vitro Activity and MIC of Sitafloxacin against Multidrug-Resistant and Extensively Drug-Resistant Mycobacterium tuberculosis Isolated in Thailand

2017 ◽  
Vol 62 (1) ◽  
Author(s):  
Manoon Leechawengwongs ◽  
Therdsak Prammananan ◽  
Sarinya Jaitrong ◽  
Pamaree Billamas ◽  
Nampueng Makhao ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Critical Concentration ◽  
Multidrug Resistant ◽  
Quinolone Resistance ◽  
Drug Resistant ◽  
Content Type ◽  
Extensively Drug Resistant ◽  
Resistant Strains ◽  
Drug Resistant Strains

ABSTRACT New fluoroquinolones (FQs) have been shown to be more active against drug-resistant Mycobacterium tuberculosis strains than early FQs, such as ofloxacin. Sitafloxacin (STFX) is a new fluoroquinolone with in vitro activity against a broad range of bacteria, including M. tuberculosis. This study aimed to determine the in vitro activity of STFX against all groups of drug-resistant strains, including multidrug-resistant M. tuberculosis (MDR M. tuberculosis), MDR M. tuberculosis with quinolone resistance (pre-XDR), and extensively drug-resistant (XDR) strains. A total of 374 drug-resistant M. tuberculosis strains were tested for drug susceptibility by the conventional proportion method, and 95 strains were randomly submitted for MIC determination using the microplate alamarBlue assay (MABA). The results revealed that all the drug-resistant strains were susceptible to STFX at a critical concentration of 2 μg/ml. Determination of the MIC90s of the strains showed different MIC levels; MDR M. tuberculosis strains had a MIC90 of 0.0625 μg/ml, whereas pre-XDR and XDR M. tuberculosis strains had identical MIC90s of 0.5 μg/ml. Common mutations within the quinolone resistance-determining region (QRDR) of gyrA and/or gyrB did not confer resistance to STFX, except that double mutations of GyrA at Ala90Val and Asp94Ala were found in strains with a MIC of 1.0 μg/ml. The results indicated that STFX had potent in vitro activity against all the groups of drug-resistant M. tuberculosis strains and should be considered a new repurposed drug for treatment of multidrug-resistant and extensively drug-resistant TB.

scholarly journals GENETIC DIVERSITY OF DRUG RESISTANT STRAINS OF MYCOBACTERIUM TUBERCULOSIS IN OMSK REGION

2017 ◽  
Vol 95 (7) ◽  
pp. 33-39
Author(s):  
O. A. Pasechnik ◽  
◽  
A. M. Dymova ◽  
V. L. Stasenko ◽  
M. P. Tatarintseva ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Mycobacterium Tuberculosis ◽  
Drug Resistant ◽  
Resistant Strains ◽  
Drug Resistant Strains

scholarly journals Snapshot of Mycobacterium tuberculosis Phylogenetics from an Indian State of Arunachal Pradesh Bordering China

2021 ◽  
Author(s):  
Rashmi S Mudliar ◽  
Umay Kulsum ◽  
Syed Beenish Rufai ◽  
Mika Umpo ◽  
Moi Nyori ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Drug Resistant ◽  
Second Line ◽  
Arunachal Pradesh ◽  
Tuberculosis Programme ◽  
Indian State ◽  
Northeastern State ◽  
Resistant Strains ◽  
Drug Resistant Strains

Uncontrolled transmission of Mycobacterium tuberculosis (M. tuberculosis, MTB) drug resistant strains is a challenge to control efforts of global tuberculosis programme. Due to increasing multi-drug resistant (MDR) cases in Arunachal Pradesh, a northeastern state of India, the tracking and tracing of these resistant MTB strains is crucial for infection control and spread of drug resistance. This study aims to correlate the phenotypic DST, genomic DST (gDST) and phylogenetic analysis of MDR-MTB strains in the region. Of total 200 suspected MDR-MTB isolates, 125(62.5%) were identified as MTB. MGIT-960 SIRE DST detected 71/125(56.8%) isolates as MDR/RR-MTB of which 22(30.9%) were detected resistant to second line drugs. Whole genome sequencing of 65 isolates and their gDST found Ser315Thr mutation in katG (35/45;77.8%) and Ser531Leu mutation in rpoB (21/41;51.2%) associated with drug resistance. SNP barcoding categorized the dataset with Lineage2 (41;63.1%) being predominant followed by Lineage3 (10;15.4%), Lineage1 (8;12.3%) and Lineage4 (6;9.2%) respectively. Phylogenetic assignment by cgMLST gave insights of two Beijing sub-lineages viz; 2.2.1 (SNP difference < 19) and 2.2.1.2 (SNP difference < 9) associated with recent ongoing transmission in Arunachal Pradesh. This study provides first insight in identifying the ongoing transmission of two virulent Beijing sub-lineages associated with TB drug resistance.

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