scholarly journals Understanding Metabolic Remodeling in Mycobacterium smegmatis to Overcome Energy Exigency and Reductive Stress Under Energy-Compromised State

2021 ◽  
Vol 12 ◽  
Author(s):  
Varsha Patil ◽  
Vikas Jain
Keyword(s):  
Mycobacterium Smegmatis ◽  
Energy Efficient ◽  
Drug Targets ◽  
Redox Homeostasis ◽  
Redox Sensor ◽  
Metabolic Remodeling ◽  
Novel Drug ◽  
Novel Drug Targets ◽  
Reduced State

Mycobacteria such as Mycobacterium tuberculosis, the causative agent of tuberculosis that annually kills several million people worldwide, and Mycobacterium smegmatis, the non-pathogenic fast-growing mycobacteria, require oxidative phosphorylation to meet their energy requirements. We have previously shown that deletion of one of the two copies of atpD gene that codes for the ATP synthase β-subunit establishes an energy-compromised state in M. smegmatis. Here we report that upon such deletion, a major routing of electron flux occurs through the less energy-efficient complexes of its respiratory chain. ΔatpD bacterium also shows an increased reduced state which is further confirmed by the overexpression of WhiB3, a major redox sensor. We show a substantial modulation of the biosynthesis of cell wall associated lipids and triacylglycerol (TAG). An accumulation of TAG-containing lipid bodies is further confirmed by using 14C oleate incorporation. Interestingly, the mutant also shows an overexpression of TAG-degrading lipase genes, and the intracellular lipolytic enzymes mediate TAG hydrolysis for their utilization as energy source. We believe that our in vitro energy-depleted model will allow us to explore the critical link between energy metabolism, redox homeostasis, and lipid biosynthesis during ATP-depleted state, which will enhance our understanding of the bacterial adaptation, and will allow us to identify novel drug targets to counter mycobacterial infections.

Innovative Methodology in the Discovery of Novel Drug Targets in the Free-Living Amoebae

2018 ◽  
Vol 20 (1) ◽  
pp. 60-69 ◽  
Author(s):  
Abdul Mannan Baig
Keyword(s):  
Drug Targets ◽  
Mortality Rates ◽  
In Vitro Assays ◽  
Cancer Drug ◽  
Cns Infection ◽  
Free Living ◽  
Drug Target Discovery ◽  
Novel Drug ◽  
Novel Drug Targets

Despite advances in drug discovery and modifications in the chemotherapeutic regimens, human infections caused by free-living amoebae (FLA) have high mortality rates (~95%). The FLA that cause fatal human cerebral infections include Naegleria fowleri, Balamuthia mandrillaris and Acanthamoeba spp. Novel drug-target discovery remains the only viable option to tackle these central nervous system (CNS) infection in order to lower the mortality rates caused by the FLA. Of these FLA, N. fowleri causes primary amoebic meningoencephalitis (PAM), while the A. castellanii and B. Mandrillaris are known to cause granulomatous amoebic encephalitis (GAE). The infections caused by the FLA have been treated with drugs like Rifampin, Fluconazole, Amphotericin-B and Miltefosine. Miltefosine is an anti-leishmanial agent and an experimental anti-cancer drug. With only rare incidences of success, these drugs have remained unsuccessful to lower the mortality rates of the cerebral infection caused by FLA. Recently, with the help of bioinformatic computational tools and the discovered genomic data of the FLA, discovery of newer drug targets has become possible. These cellular targets are proteins that are either unique to the FLA or shared between the humans and these unicellular eukaryotes. The latter group of proteins has shown to be targets of some FDA approved drugs prescribed in non-infectious diseases. This review out-lines the bioinformatics methodologies that can be used in the discovery of such novel drug-targets, their chronicle by in-vitro assays done in the past and the translational value of such target discoveries in human diseases caused by FLA.

scholarly journals Bioorganometallic Compounds as Novel Drug Targets against Schistosomiasis in Sub-Saharan Africa: An alternative to Praziquantel?

2021 ◽  
Author(s):  
Cuma Cumisa Ndamse ◽  
Priscilla Masamba ◽  
Abidemi Paul Kappo
Keyword(s):  
Drug Resistance ◽  
Drug Targets ◽  
Redox Homeostasis ◽  
Organometallic Compounds ◽  
Sub Saharan Africa ◽  
Redox Biology ◽  
Anti Cancer ◽  
Sub Saharan ◽  
Novel Drug ◽  
Novel Drug Targets

Human schistosomiasis is a disease that mostly plagues the destitute of various tropical and sub-tropical countries, particularly in sub-Saharan Africa and South America. It has significant effects on various health and economic-related matters. Globally, the burden of schistosomiasis has been controlled with a single chemotherapeutic drug, Praziquantel, which has recently demonstrated several clinical issues, including its inability to destroy juvenile schistosome worms and drug resistance because of its extensive use. The use of organometallic moieties in biological and medicinal chemistry has developed greatly and has led to their use in various anti-cancer and anti-infectious agents. The abundance of a range of organometallic compounds that can cause damage to the parasite has received tremendous feedback, with many already at clinical trials. The distinct redox biology of the schistosome parasite is a vulnerable element to the survival of the worm and has steered attempts toward the use of redox-directed bioorganometallic compounds. Disruption of the schistosome redox homeostasis through organometallic ions provides a novel drug target that could be used in overcoming the drawbacks of the mainstream drug and one that could possibly bypass the emergence of drug resistance.

Novel drug targets for asthma and COPD: Lessons learned from in vitro and in vivo models

2014 ◽  
Vol 29 (2) ◽  
pp. 181-198 ◽  
Author(s):  
Katie E. Baker ◽  
Sara J. Bonvini ◽  
Chantal Donovan ◽  
Rachel E. Foong ◽  
Bing Han ◽  
...  
Keyword(s):  
Drug Targets ◽  
Lessons Learned ◽  
In Vivo Models ◽  
Novel Drug ◽  
Novel Drug Targets

Mining the Proteome of Streptococcus mutans for Putative Drug Targets

2020 ◽  
Vol 20 ◽  
Author(s):  
Shakti Chandra Vadhana Marimuthu ◽  
Haribalaganesh Ravinarayanan ◽  
Joseph Christina Rosy ◽  
Krishnan Sundar
Keyword(s):  
Dental Caries ◽  
Streptococcus Mutans ◽  
Drug Targets ◽  
In Vitro Selection ◽  
Target Identification ◽  
Dental Enamel ◽  
Dental Tissues ◽  
Novel Drug ◽  
Novel Drug Targets

Background: Dental caries is the most common and one of the prevalent diseases in the world. Streptococcus mutans is one of the major oral pathogen that causes dental caries by forming biofilm on dental tissues, degrading dental enamel and consequent cavitation in the tissue. In vitro selection of drug targets is a laborious and expensive process and therefore computational methods are preferable for target identification at initial stage. Objective: The present research aims to find new drug targets in S. mutans by using subtractive proteomics analysis which implements various bioinformatics tools and databases. Methods: The proteome of S. mutans UA159 was mined for novel drug targets using computational tools and databases such as: CD-HIT, BLASTP, DEG, KAAS and CELL2GO. Results: Out of 1953 proteins of S. mutans UA159, proteins that are non-redundant, non-homologous to human and nonessential to the pathogen were eliminated. Around 178 proteins already available in drug target repositories were also eliminated. Possible functions and subcellular localization of 32 uncharacterized proteins were predicted. Substantially 13 proteins were identified as novel drug targets in S. mutans UA159 that can be targeted by various drugs against dental caries. Conclusion: This study will effectuate the development of novel therapeutic agents against dental carries and other Streptococcal infections.

scholarly journals To Discover the Efficient and Novel Drug Targets in Human Cancers Using CRISPR/Cas Screening and Databases

2021 ◽  
Vol 22 (22) ◽  
pp. 12322
Author(s):  
Iichiroh Onishi ◽  
Kouhei Yamamoto ◽  
Yuko Kinowaki ◽  
Masanobu Kitagawa ◽  
Morito Kurata
Keyword(s):  
Drug Targets ◽  
Gene Editing ◽  
Synthetic Lethality ◽  
Cancer Therapies ◽  
Human Cancers ◽  
Genetic Abnormalities ◽  
Ideal Tool ◽  
Novel Drug ◽  
Novel Drug Targets

CRISPR/Cas has emerged as an excelle nt gene-editing technology and is used worldwide for research. The CRISPR library is an ideal tool for identifying essential genes and synthetic lethality targeted for cancer therapies in human cancers. Synthetic lethality is defined as multiple genetic abnormalities that, when present individually, do not affect function or survival, but when present together, are lethal. Recently, many CRISPR libraries are available, and the latest libraries are more accurate and can be applied to few cells. However, it is easier to efficiently search for cancer targets with their own screenings by effectively using databases of CRISPR screenings, such as Depmap portal, PICKLES (Pooled In-Vitro CRISPR Knockout Library Essentiality Screens), iCSDB, Project Score database, and CRISP-view. This review will suggest recent optimal CRISPR libraries and effective databases for Novel Approaches in the Discovery and Design of Targeted Therapies.

Novel drug targets in 2019

2020 ◽  
Vol 19 (5) ◽  
pp. 300-300 ◽  
Author(s):  
Sorin Avram ◽  
Liliana Halip ◽  
Ramona Curpan ◽  
Tudor I. Oprea
Keyword(s):  
Drug Targets ◽  
Novel Drug ◽  
Novel Drug Targets

Polyamines and Related Nitrogen Compounds in the Chemotherapy of Neglected Diseases Caused by Kinetoplastids

2018 ◽  
Vol 18 (5) ◽  
pp. 321-368 ◽  
Author(s):  
Juan A. Bisceglia ◽  
Maria C. Mollo ◽  
Nadia Gruber ◽  
Liliana R. Orelli
Keyword(s):  
Drug Targets ◽  
Redox Homeostasis ◽  
Cost Effective ◽  
Structural Features ◽  
Mammalian Host ◽  
Neglected Diseases ◽  
Nitrogen Compounds ◽  
Chemical Structures

Neglected diseases due to the parasitic protozoa Leishmania and Trypanosoma (kinetoplastids) affect millions of people worldwide, and the lack of suitable treatments has promoted an ongoing drug discovery effort to identify novel nontoxic and cost-effective chemotherapies. Polyamines are ubiquitous small organic molecules that play key roles in kinetoplastid parasites metabolism, redox homeostasis and in the normal progression of cell cycles, which differ from those found in the mammalian host. These features make polyamines attractive in terms of antiparasitic drug development. The present work provides a comprehensive insight on the use of polyamine derivatives and related nitrogen compounds in the chemotherapy of kinetoplastid diseases. The amount of literature on this subject is considerable, and a classification considering drug targets and chemical structures were made. Polyamines, aminoalcohols and basic heterocycles designed to target the relevant parasitic enzyme trypanothione reductase are discussed in the first section, followed by compounds directed to less common targets, like parasite SOD and the aminopurine P2 transporter. Finally, the third section comprises nitrogen compounds structurally derived from antimalaric agents. References on the chemical synthesis of the selected compounds are reported together with their in vivo and/or in vitro IC50 values, and structureactivity relationships within each group are analyzed. Some favourable structural features were identified from the SAR analyses comprising protonable sites, hydrophobic groups and optimum distances between them. The importance of certain pharmacophoric groups or amino acid residues in the bioactivity of polyamine derived compounds is also discussed.

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