scholarly journals Erratum: Data Intensive Genome Level Analysis for Identifying Novel, Non-Toxic Drug Targets for Multi Drug Resistant Mycobacterium tuberculosis

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Divneet Kaur ◽  
Rintu Kutum ◽  
Debasis Dash ◽  
Samir K. Brahmachari
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Targets ◽  
Drug Resistant ◽  
Data Intensive ◽  
Toxic Drug ◽  
Genome Level ◽  
Level Analysis

scholarly journals Data Intensive Genome Level Analysis for Identifying Novel, Non-Toxic Drug Targets for Multi Drug Resistant Mycobacterium tuberculosis

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Divneet Kaur ◽  
Rintu Kutum ◽  
Debasis Dash ◽  
Samir K. Brahmachari
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Discovery ◽  
Drug Targets ◽  
Systems Approach ◽  
Data Bank ◽  
Data Intensive ◽  
Synonymous Mutations ◽  
Starting Point ◽  
Genome Level ◽  
Level Analysis

Abstract We report the construction of a novel Systems Biology based virtual drug discovery model for the prediction of non-toxic metabolic targets in Mycobacterium tuberculosis (Mtb). This is based on a data-intensive genome level analysis and the principle of conservation of the evolutionarily important genes. In the 1623 sequenced Mtb strains, 890 metabolic genes identified through a systems approach in Mtb were evaluated for non-synonymous mutations. The 33 genes showed none or one variation in the entire 1623 strains, including 1084 Russian MDR strains. These invariant targets were further evaluated for their experimental and in silico essentiality as well as availability of their crystal structure in Protein Data Bank (PDB). Along with this, targets for the common existing antibiotics and the new Tb drug candidates were also screened for their variation across 1623 strains of Mtb for understanding the drug resistance. We propose that the reduced set of these reported targets could be a more effective starting point for medicinal chemists in generating new chemical leads. This approach has the potential of fueling the dried up Tuberculosis (Tb) drug discovery pipeline.

scholarly journals Label-Free Comparative Proteomics of Differentially Expressed Mycobacterium tuberculosis Protein in Rifampicin-Related Drug-Resistant Strains

Pathogens ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 607
Author(s):  
Nadeem Ullah ◽  
Ling Hao ◽  
Jo-Lewis Banga Ndzouboukou ◽  
Shiyun Chen ◽  
Yaqi Wu ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Targets ◽  
Control Strategies ◽  
Multidrug Resistant ◽  
Differentially Expressed ◽  
Effective Control ◽  
Drug Resistant ◽  
Differentially Expressed Proteins ◽  
Label Free ◽  
Candidate Target

Rifampicin (RIF) is one of the most important first-line anti-tuberculosis (TB) drugs, and more than 90% of RIF-resistant (RR) Mycobacterium tuberculosis clinical isolates belong to multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB. In order to identify specific candidate target proteins as diagnostic markers or drug targets, differential protein expression between drug-sensitive (DS) and drug-resistant (DR) strains remains to be investigated. In the present study, a label-free, quantitative proteomics technique was performed to compare the proteome of DS, RR, MDR, and XDR clinical strains. We found iniC, Rv2141c, folB, and Rv2561 were up-regulated in both RR and MDR strains, while fadE9, espB, espL, esxK, and Rv3175 were down-regulated in the three DR strains when compared to the DS strain. In addition, lprF, mce2R, mce2B, and Rv2627c were specifically expressed in the three DR strains, and 41 proteins were not detected in the DS strain. Functional category showed that these differentially expressed proteins were mainly involved in the cell wall and cell processes. When compared to the RR strain, Rv2272, smtB, lpqB, icd1, and folK were up-regulated, while esxK, PPE19, Rv1534, rpmI, ureA, tpx, mpt64, frr, Rv3678c, esxB, esxA, and espL were down-regulated in both MDR and XDR strains. Additionally, nrp, PPE3, mntH, Rv1188, Rv1473, nadB, PPE36, and sseA were specifically expressed in both MDR and XDR strains, whereas 292 proteins were not identified when compared to the RR strain. When compared between MDR and XDR strains, 52 proteins were up-regulated, while 45 proteins were down-regulated in the XDR strain. 316 proteins were especially expressed in the XDR strain, while 92 proteins were especially detected in the MDR strain. Protein interaction networks further revealed the mechanism of their involvement in virulence and drug resistance. Therefore, these differentially expressed proteins are of great significance for exploring effective control strategies of DR-TB.

scholarly journals 194 Designing non-toxic ligands against TB using data intensive genome level analysis

2015 ◽  
Vol 33 (sup1) ◽  
pp. 128-128
Author(s):  
Divneet Kaur ◽  
S.K. Brahmachari
Keyword(s):  
Data Intensive ◽  
Genome Level ◽  
Using Data ◽  
Level Analysis

scholarly journals Azetidines kill Mycobacterium tuberculosis without detectable resistance by blocking mycolate assembly

2020 ◽  
Author(s):  
Alice Lanne ◽  
Yixin Cui ◽  
Edward Browne ◽  
Philip G. E. Craven ◽  
Nicholas J. Cundy ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Mode Of Action ◽  
Drug Targets ◽  
Cell Envelope ◽  
Mycolic Acid ◽  
New Drugs ◽  
Drug Resistant ◽  
Target Deconvolution ◽  
Mdr Tb ◽  
Mycobacterial Cell Wall

AbstractTuberculosis (TB) is the leading cause of global morbidity and mortality resulting from infectious disease, with over 10 million new cases and 1.5 million deaths in 2019. This global emergency is exacerbated by the emergence of multi-drug-resistant MDR-TB and extensively-drug-resistant XDR-TB, therefore new drugs and new drug targets are urgently required. From a whole-cell phenotypic screen a series of azetidines derivatives termed BGAz, that elicit potent bactericidal activity with MIC99 values <10 μM against drug-sensitive Mycobacterium tuberculosis and MDR-TB were identified. These compounds demonstrate no detectable drug resistance. Mode of action and target deconvolution studies suggest that these compounds inhibit mycobacterial growth by interfering with cell envelope biogenesis, specifically late-stage mycolic acid biosynthesis. Transcriptomic analysis demonstrates that the BGAz compounds tested display a mode of action distinct from existing mycobacterial cell-wall inhibitors. In addition, the compounds tested exhibit toxicological and PK/PD profiles that pave the way for their development as anti-tubercular chemotherapies.

scholarly journals Discovery of Common Putative Drug Targets and Vaccine Candidates for Mycobacterium tuberculosis sp.

2019 ◽  
Vol 9 (2-s) ◽  
pp. 67-71 ◽  
Author(s):  
Ravina Madhulitha Nalamolu ◽  
Chiranjeevi Pasala ◽  
Sudheer Kumar Katari ◽  
Umamaheswari Amineni
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Targets ◽  
Confidence Score ◽  
Drug Resistant ◽  
Gene Products ◽  
High Confidence ◽  
Resistant Tuberculosis ◽  
Proteomic Approach ◽  
Therapeutic Development ◽  
Conserved Gene

ABSTRACT Mycobacterium tuberculosis is the bacteria that cause tuberculosis (TB), an infection that usually affects the lungs and can be fatal without proper treatment. Combating through available drugs became a difficult task due to drug resistance and lack of appropriate common targets against genetically diverse strains. Since to improve efficacy, the effective targets should be identified and critically assessed. In the study, we aim to predict the potential novel targets against M. tuberculosis strains by employing in silico approach. The complete proteomic datasets of 23 M. tuberculosis strains was comparatively processed by executing R-scripts and eventually predicted 3906 'conserved gene products'. Further, we performed subtractive proteomic approach in search of promising crucial targets. Consequently, eight enzymes and two membrane proteins were prioritized as new therapeutic and vaccine targets respectively which found to have more interactors in network with high-confidence score, druggability and antigenicity. Therefore, outcomes of the study emphasize the importance of new targets may counteract with false-positive/negatives and facilitate appropriate potential targets for a new insight of reliable therapeutic development. Key words: Mycobacterium tuberculosis, Multidrug resistance tuberculosis and Extensive drug resistant tuberculosis.

Mycobacterium tuberculosis cytochrome P450 enzymes: a cohort of novel TB drug targets

2012 ◽  
Vol 40 (3) ◽  
pp. 573-579 ◽  
Author(s):  
Sean A. Hudson ◽  
Kirsty J. McLean ◽  
Andrew W. Munro ◽  
Chris Abell
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Cytochrome P450 ◽  
High Throughput Screening ◽  
Drug Targets ◽  
Drug Resistant ◽  
Cytochrome P450 Enzymes ◽  
Front Line ◽  
Exciting Potential ◽  
Tuberculosis Disease ◽  
Fragment Based Drug Discovery

TB (tuberculosis) disease remains responsible for the death of over 1.5 million people each year. The alarming emergence of drug-resistant TB has sparked a critical need for new front-line TB drugs with a novel mode of action. In the present paper, we review recent genomic and biochemical evidence implicating Mycobacterium tuberculosis CYP (cytochrome P450) enzymes as exciting potential targets for new classes of anti-tuberculars. We also discuss HTS (high-throughput screening) and fragment-based drug-discovery campaigns that are being used to probe their potential druggability.

Focusing on DNA Repair and Damage Tolerance Mechanisms in Mycobacterium tuberculosis: An Emerging Therapeutic Theme

2020 ◽  
Vol 20 (5) ◽  
pp. 390-408 ◽  
Author(s):  
Pooja Mittal ◽  
Rajesh Sinha ◽  
Amit Kumar ◽  
Pooja Singh ◽  
Moses Rinchui Ngasainao ◽  
...  
Keyword(s):  
Dna Repair ◽  
Mycobacterium Tuberculosis ◽  
Drug Targets ◽  
Damage Tolerance ◽  
Patient Adherence ◽  
Drug Regimen ◽  
Drug Resistant ◽  
Long Duration ◽  
Resistant Strains ◽  
Drug Resistant Strains

Tuberculosis (TB) is one such disease that has become a nuisance in the world scenario and one of the most deadly diseases of the current times. The etiological agent of tuberculosis, Mycobacterium tuberculosis (M. tb) kills millions of people each year. Not only 1.7 million people worldwide are estimated to harbor M. tb in the latent form but also 5 to 15 percent of which are expected to acquire an infection during a lifetime. Though curable, a long duration of drug regimen and expense leads to low patient adherence. The emergence of multi-, extensive- and total- drug-resistant strains of M. tb further complicates the situation. Owing to high TB burden, scientists worldwide are trying to design novel therapeutics to combat this disease. Therefore, to identify new drug targets, there is a growing interest in targeting DNA repair pathways to fight this infection. Thus, this review aims to explore DNA repair and damage tolerance as an efficient target for drug development by understanding M. tb DNA repair and tolerance machinery and its regulation, its role in pathogenesis and survival, mutagenesis, and consequently, in the development of drug resistance.

scholarly journals Genome analyses of 174 strains of Mycobacterium tuberculosis provide insight into the evolution of drug resistance and reveal potential drug targets

2021 ◽  
Vol 7 (3) ◽  
Author(s):  
Helianthous Verma ◽  
Shekhar Nagar ◽  
Shivani Vohra ◽  
Shubhanshu Pandey ◽  
Devi Lal ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Target ◽  
Drug Targets ◽  
Type Species ◽  
Close Association ◽  
Drug Resistant ◽  
Potential Drug ◽  
Sequence Alignments ◽  
Content Type ◽  
Link Type

Mycobacterium tuberculosis is a known human pathogen that causes the airborne infectious disease tuberculosis (TB). Every year TB infects millions of people worldwide. The emergence of multi-drug resistant (MDR), extensively drug resistant (XDR) and totally drug resistant (TDR) M. tuberculosis strains against the first- and second-line anti-TB drugs has created an urgent need for the development and implementation of new drug strategies. In this study, the complete genomes of 174 strains of M. tuberculosis are analysed to understand the evolution of molecular drug target (MDT) genes. Phylogenomic placements of M. tuberculosis strains depicted close association and temporal clustering. Selection pressure analysis by deducing the ratio of non-synonymous to synonymous substitution rates (dN/dS) in 51 MDT genes of the 174 M . tuberculosis strains led to categorizing these genes into diversifying (D, dN/dS>0.70), moderately diversifying (MD, dN/dS=0.35–0.70) and stabilized (S, dN/dS<0.35) genes. The genes rpsL, gidB, pncA and ahpC were identified as diversifying, and Rv0488, kasA, ndh, ethR, ethA, embR and ddn were identified as stabilized genes. Furthermore, sequence similarity networks were drawn that supported these divisions. In the multiple sequence alignments of diversifying and stabilized proteins, previously reported resistance mutations were checked to predict sensitive and resistant strains of M. tuberculosis . Finally, to delineate the potential of stabilized or least diversified genes/proteins as anti-TB drug targets, protein–protein interactions of MDT proteins with human proteins were analysed. We predict that kasA (dN/dS=0.29), a stabilized gene that encodes the most host-interacting protein, KasA, should serve as a potential drug target for the treatment of TB.

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