A systemic approach to explore the mechanisms of drug resistance and altered signaling cascades in extensively drug-resistant tuberculosis.

Bacterial Proteins / genetics Drug Resistance, Bacterial / genetics Extensively Drug-Resistant Tuberculosis / genetics Gene Expression Regulation, Bacterial Humans Mycobacterium tuberculosis Systems Biology
Capreomycin Cluego Cluepedia Extensively drug-resistant Functional enrichment analysis Gene ontology Isoniazid Mechanisms Mycobacterium tuberculosis Regulatory networks Rifampicin

Journal

Advances in protein chemistry and structural biology
ISSN: 1876-1631
Titre abrégé: Adv Protein Chem Struct Biol
Pays: Netherlands
ID NLM: 101497281

Informations de publication

Date de publication:
2021
Historique:
entrez: 3 8 2021
pubmed: 4 8 2021
medline: 3 9 2021
Statut: ppublish

Résumé

The persistence of extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis (MTB) continue to pose a significant challenge to the treatment and control of tuberculosis infections worldwide. XDR-MTB strains exhibit resistance against first-line anti-TB drugs, fluoroquinolones, and second-line injectable drugs. The mechanisms of drug resistance of MTB remains poorly understood. Our study aims at identifying the differentially expressed genes (DEGs), associated gene networks, and signaling cascades involved in rendering this pathogen resistant to multiple drugs, namely, isoniazid, rifampicin, and capreomycin. We used the microarray dataset GSE53843. The GEO2R tool was used to prioritize the most significant DEGs (top 250) of each drug exposure sample between XDR strains and non-resistant strains. The validation of the 250 DEGs was performed using volcano plots. Protein-protein interaction networks of the DEGs were created using STRING and Cytoscape tools, which helped decipher the relationship between these genes. The significant DEGs were functionally annotated using DAVID and ClueGO. The concomitant biological processes (BP) and molecular functions (MF) were represented as dot plots. We identified relevant molecular pathways and biological processes, such as cell wall biogenesis, lipid metabolic process, ion transport, phosphopantetheine binding, and triglyceride lipase activity. These processes indicated the involvement of multiple interconnected mechanisms in drug resistance. Our study highlighted the impact of cell wall permeability, with the dysregulation of the mur family of proteins, as essential factors in the inference of resistance. Additionally, upregulation of genes responsible for ion transport such as ctpF, arsC, and nark3, emphasizes the importance of transport channels and efflux pumps in potentially driving out stress-inducing compounds. This study investigated the upregulation of the Lip family of proteins, which play a crucial role in triglyceride lipase activity. Thereby illuminating the potential role of drug-induced dormancy and subsequent resistance in the mycobacterial strains. Multiple mechanisms such as carboxylic acid metabolic process, NAD biosynthetic process, triglyceride lipase activity, phosphopantetheine binding, organic acid biosynthetic process, and growth of symbiont in host cell were observed to partake in resistance of XDR-MTB. This study ultimately provides a platform for important mapping targets for potential therapeutics against XDR-MTB.

Sections du résumé

BACKGROUND AND AIM
The persistence of extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis (MTB) continue to pose a significant challenge to the treatment and control of tuberculosis infections worldwide. XDR-MTB strains exhibit resistance against first-line anti-TB drugs, fluoroquinolones, and second-line injectable drugs. The mechanisms of drug resistance of MTB remains poorly understood. Our study aims at identifying the differentially expressed genes (DEGs), associated gene networks, and signaling cascades involved in rendering this pathogen resistant to multiple drugs, namely, isoniazid, rifampicin, and capreomycin.
METHODS
We used the microarray dataset GSE53843. The GEO2R tool was used to prioritize the most significant DEGs (top 250) of each drug exposure sample between XDR strains and non-resistant strains. The validation of the 250 DEGs was performed using volcano plots. Protein-protein interaction networks of the DEGs were created using STRING and Cytoscape tools, which helped decipher the relationship between these genes. The significant DEGs were functionally annotated using DAVID and ClueGO. The concomitant biological processes (BP) and molecular functions (MF) were represented as dot plots.
RESULTS AND CONCLUSION
We identified relevant molecular pathways and biological processes, such as cell wall biogenesis, lipid metabolic process, ion transport, phosphopantetheine binding, and triglyceride lipase activity. These processes indicated the involvement of multiple interconnected mechanisms in drug resistance. Our study highlighted the impact of cell wall permeability, with the dysregulation of the mur family of proteins, as essential factors in the inference of resistance. Additionally, upregulation of genes responsible for ion transport such as ctpF, arsC, and nark3, emphasizes the importance of transport channels and efflux pumps in potentially driving out stress-inducing compounds. This study investigated the upregulation of the Lip family of proteins, which play a crucial role in triglyceride lipase activity. Thereby illuminating the potential role of drug-induced dormancy and subsequent resistance in the mycobacterial strains. Multiple mechanisms such as carboxylic acid metabolic process, NAD biosynthetic process, triglyceride lipase activity, phosphopantetheine binding, organic acid biosynthetic process, and growth of symbiont in host cell were observed to partake in resistance of XDR-MTB. This study ultimately provides a platform for important mapping targets for potential therapeutics against XDR-MTB.

Identifiants

DOI: 10.1016/bs.apcsb.2021.02.002 PMID: 34340773
pubmed: 34340773
pii: S1876-1623(21)00020-1
doi: 10.1016/bs.apcsb.2021.02.002
pii:
doi:

Substances chimiques

Bacterial Proteins 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

343-364

Informations de copyright

Copyright © 2021 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Conflict of interest The authors have declared that no conflicts of interest exist.

Auteurs

S Udhaya Kumar (S)

School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India.

Aisha Saleem (A)

School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India.

D Thirumal Kumar (D)

Department of Bioinformatics, Saveetha School of Engineering, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India.

V Anu Preethi (V)

School of Computer Science and Engineering, Vellore Institute of Technology, Vellore, Tamil Nadu, India.

Salma Younes (S)

Translational Research Institute, Women's Wellness and Research Center, Hamad Medical Corporation, Doha, Qatar.

Hatem Zayed (H)

Department of Biomedical Sciences, College of Health and Sciences, QU Health, Qatar University, Doha, Qatar.

Iftikhar Aslam Tayubi (IA)

Faculty of Computing and Information Technology, King Abdul-Aziz University, Rabigh, Saudi Arabia.

C George Priya Doss (C)

School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India. Electronic address: georgepriyadoss@vit.ac.in.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines bactériennes › A systemic approach to explore the mechanisms...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Résistance aux substances › Résistance microbienne aux médicaments › Résistance bactérienne aux médicaments › A systemic approach to explore the mechanisms...
questionsmedicales.fr › Infection › Infections bactériennes et mycoses › Infections bactériennes › Infections bactériennes à Gram positif › Infections à Actinomycetales › Infections à Mycobacterium › Tuberculose › Tuberculose multirésistante › Tuberculose ultrarésistante aux médicaments › A systemic approach to explore the mechanisms...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Régulation de l'expression des gènes bactériens › A systemic approach to explore the mechanisms...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › A systemic approach to explore the mechanisms...
questionsmedicales.fr › Bactéries › Bactéries à Gram positif › Bâtonnets à Gram positif › Bâtonnets asporogènes à Gram positif › Bâtonnets asporogènes réguliers à Gram positif › Mycobacteriaceae › Mycobacterium › Mycobacterium tuberculosis › A systemic approach to explore the mechanisms...
questionsmedicales.fr › Disciplines des sciences naturelles › Disciplines des sciences biologiques › Biologie › Biologie des systèmes › A systemic approach to explore the mechanisms...