scholarly journals Oxidative Phosphorylation—an Update on a New, Essential Target Space for Drug Discovery in Mycobacterium tuberculosis

2020 ◽  
Vol 10 (7) ◽  
pp. 2339 ◽  
Author(s):  
Caroline Shi-Yan Foo ◽  
Kevin Pethe ◽  
Andréanne Lupien
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Discovery ◽  
Oxidative Phosphorylation ◽  
New Drugs ◽  
Target Space ◽  
Future Directions ◽  
Tb Treatment ◽  
Fda Approval ◽  
The Subject ◽  
Synthase Inhibitor

New drugs with new mechanisms of action are urgently required to tackle the global tuberculosis epidemic. Following the FDA-approval of the ATP synthase inhibitor bedaquiline (Sirturo®), energy metabolism has become the subject of intense focus as a novel pathway to exploit for tuberculosis drug development. This enthusiasm stems from the fact that oxidative phosphorylation (OxPhos) and the maintenance of the transmembrane electrochemical gradient are essential for the viability of replicating and non-replicating Mycobacterium tuberculosis (M. tb), the etiological agent of human tuberculosis (TB). Therefore, new drugs targeting this pathway have the potential to shorten TB treatment, which is one of the major goals of TB drug discovery. This review summarises the latest and key findings regarding the OxPhos pathway in M. tb and provides an overview of the inhibitors targeting various components. We also discuss the potential of new regimens containing these inhibitors, the flexibility of this pathway and, consequently, the complexity in targeting it. Lastly, we discuss opportunities and future directions of this drug target space.

scholarly journals Oxidative Phosphorylation as a Target Space for Tuberculosis: Success, Caution, and Future Directions

2017 ◽  
Vol 5 (3) ◽  
Author(s):  
Gregory M. Cook ◽  
Kiel Hards ◽  
Elyse Dunn ◽  
Adam Heikal ◽  
Yoshio Nakatani ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Target Space ◽  
Future Directions

scholarly journals Oxidative Phosphorylation as a Target Space for Tuberculosis: Success, Caution, and Future Directions

2017 ◽  
pp. 295-316 ◽  
Author(s):  
Gregory M. Cook ◽  
Kiel Hards ◽  
Elyse Dunn ◽  
Adam Heikal ◽  
Yoshio Nakatani ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Target Space ◽  
Future Directions

scholarly journals The Combination of Sulfamethoxazole, Trimethoprim, and Isoniazid or Rifampin Is Bactericidal and Prevents the Emergence of Drug Resistance in Mycobacterium tuberculosis

2012 ◽  
Vol 56 (10) ◽  
pp. 5142-5148 ◽  
Author(s):  
Catherine Vilchèze ◽  
William R. Jacobs
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Multidrug Resistant ◽  
New Drugs ◽  
Drug Resistant ◽  
Content Type ◽  
The Past ◽  
Tb Treatment

ABSTRACTThe challenges of developing new drugs to treat tuberculosis (TB) are indicated by the relatively small number of candidates entering clinical trials in the past decade. To overcome these issues, we reexamined two FDA-approved antibacterial drugs, sulfamethoxazole (SMX) and trimethoprim (TMP), for use in TB treatment. SMX and TMP inhibit folic acid biosynthesis and are used in combination to treat infections of the respiratory, urinary, and gastrointestinal tracts. The MICs of SMX and TMP, alone and in combination, were determined for drug-susceptible, multidrug-resistant (MDR), and extensively drug-resistantMycobacterium tuberculosisstrains. While TMP alone was not effective againstM. tuberculosis, the combination of TMP and SMX was bacteriostatic againstM. tuberculosis. Surprisingly, the combination of SMX and TMP was also active against a subset of MDRM. tuberculosisstrains. Treatment ofM. tuberculosiswith TMP-SMX and a first-line anti-TB drug, either isoniazid or rifampin, was bactericidal, demonstrating that the combination of TMP and SMX with isoniazid or rifampin was not antagonistic. Moreover, the addition of SMX-TMP in combination with either isoniazid or rifampin also prevented the emergence of drug resistancein vitro. In conclusion, this study further illustrates the opportunity to reevaluate the activity of TMP-SMXin vivoto prevent the emergence of drug-resistantM. tuberculosis.

scholarly journals Targeting Energy Metabolism in Mycobacterium tuberculosis, a New Paradigm in Antimycobacterial Drug Discovery

mBio ◽  
2017 ◽  
Vol 8 (2) ◽  
Author(s):  
Dirk Bald ◽  
Cristina Villellas ◽  
Ping Lu ◽  
Anil Koul
Keyword(s):  
Drug Discovery ◽  
Energy Metabolism ◽  
Oxidative Phosphorylation ◽  
Multidrug Resistant ◽  
New Paradigm ◽  
Mycobacterial Infections ◽  
Highly Active ◽  
Oxidative Phosphorylation Pathway ◽  
Novel Target ◽  
Synthase Inhibitor

ABSTRACT Drug-resistant mycobacterial infections are a serious global health challenge, leading to high mortality and socioeconomic burdens in developing countries worldwide. New innovative approaches, from identification of new targets to discovery of novel chemical scaffolds, are urgently needed. Recently, energy metabolism in mycobacteria, in particular the oxidative phosphorylation pathway, has emerged as an object of intense microbiological investigation and as a novel target pathway in drug discovery. New classes of antibacterials interfering with elements of the oxidative phosphorylation pathway are highly active in combating dormant or latent mycobacterial infections, with a promise of shortening tuberculosis chemotherapy. The regulatory approval of the ATP synthase inhibitor bedaquiline and the discovery of Q203, a candidate drug targeting the cytochrome bc 1 complex, have highlighted the central importance of this new target pathway. In this review, we discuss key features and potential applications of inhibiting energy metabolism in our quest for discovering potent novel and sterilizing drug combinations for combating tuberculosis. We believe that the combination of drugs targeting elements of the oxidative phosphorylation pathway can lead to a completely new regimen for drug-susceptible and multidrug-resistant tuberculosis.

scholarly journals Bengamides display potent activity against drug-resistant Mycobacterium tuberculosis

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Diana H. Quan ◽  
Gayathri Nagalingam ◽  
Ian Luck ◽  
Nicholas Proschogo ◽  
Vijaykumar Pillalamarri ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
New Drugs ◽  
Bioactive Molecules ◽  
Aminopeptidase Activity ◽  
Drug Resistant ◽  
Lead Compounds ◽  
New Class ◽  
Tb Treatment ◽  
Bioassay Guided Fractionation

Abstract Mycobacterium tuberculosis infects over 10 million people annually and kills more people each year than any other human pathogen. The current tuberculosis (TB) vaccine is only partially effective in preventing infection, while current TB treatment is problematic in terms of length, complexity and patient compliance. There is an urgent need for new drugs to combat the burden of TB disease and the natural environment has re-emerged as a rich source of bioactive molecules for development of lead compounds. In this study, one species of marine sponge from the Tedania genus was found to yield samples with exceptionally potent activity against M. tuberculosis. Bioassay-guided fractionation identified bengamide B as the active component, which displayed activity in the nanomolar range against both drug-sensitive and drug-resistant M. tuberculosis. The active compound inhibited in vitro activity of M. tuberculosis MetAP1c protein, suggesting the potent inhibitory action may be due to interference with methionine aminopeptidase activity. Tedania-derived bengamide B was non-toxic against human cell lines, synergised with rifampicin for in vitro inhibition of bacterial growth and reduced intracellular replication of M. tuberculosis. Thus, bengamides isolated from Tedania sp. show significant potential as a new class of compounds for the treatment of drug-resistant M. tuberculosis.

History of the Study of Apocrypha in Early Medieval England

2020 ◽  
Vol 48 (3-4) ◽  
pp. 13-26
Author(s):  
Brandon W. Hawk
Keyword(s):  
Old Testament ◽  
Medieval England ◽  
Medieval Period ◽  
Early Medieval ◽  
Future Directions ◽  
Early Judaism ◽  
Wide Range ◽  
History Of ◽  
The Subject ◽  
Early English

Literature written in England between about 500 and 1100 CE attests to a wide range of traditions, although it is clear that Christian sources were the most influential. Biblical apocrypha feature prominently across this corpus of literature, as early English authors clearly relied on a range of extra-biblical texts and traditions related to works under the umbrella of what have been called “Old Testament Pseudepigrapha” and “New Testament/Christian Apocrypha." While scholars of pseudepigrapha and apocrypha have long trained their eyes upon literature from the first few centuries of early Judaism and early Christianity, the medieval period has much to offer. This article presents a survey of significant developments and key threads in the history of scholarship on apocrypha in early medieval England. My purpose is not to offer a comprehensive bibliography, but to highlight major studies that have focused on the transmission of specific apocrypha, contributed to knowledge about medieval uses of apocrypha, and shaped the field from the nineteenth century up to the present. Bringing together major publications on the subject presents a striking picture of the state of the field as well as future directions.

Oxazole-Based Compounds As Anticancer Agents

2020 ◽  
Vol 26 (41) ◽  
pp. 7337-7371 ◽  
Author(s):  
Maria A. Chiacchio ◽  
Giuseppe Lanza ◽  
Ugo Chiacchio ◽  
Salvatore V. Giofrè ◽  
Roberto Romeo ◽  
...  
Keyword(s):  
Cancer Research ◽  
Drug Discovery ◽  
Anticancer Agents ◽  
Heterocyclic Compounds ◽  
Chemical Diversity ◽  
Biologically Active ◽  
New Drugs ◽  
The Core ◽  
Anti Cancer ◽  
Biologically Active Derivatives

: Heterocyclic compounds represent a significant target for anti-cancer research and drug discovery, due to their structural and chemical diversity. Oxazoles, with oxygen and nitrogen atoms present in the core structure, enable various types of interactions with different enzymes and receptors, favoring the discovery of new drugs. Aim of this review is to describe the most recent reports on the use of oxazole-based compounds in anticancer research, with reference to the newly discovered iso/oxazole-based drugs, to their synthesis and to the evaluation of the most biologically active derivatives. The corresponding dehydrogenated derivatives, i.e. iso/oxazolines and iso/oxazolidines, are also reported.

Recent Advances in Drug Repurposing for Parkinson’s Disease

2019 ◽  
Vol 26 (28) ◽  
pp. 5340-5362 ◽  
Author(s):  
Xin Chen ◽  
Giuseppe Gumina ◽  
Kristopher G. Virga
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Drug Discovery ◽  
De Novo ◽  
Drug Repositioning ◽  
Drug Repurposing ◽  
Cost Effective ◽  
New Drugs ◽  
Recent Advances ◽  
Clinical Drugs

:As a long-term degenerative disorder of the central nervous system that mostly affects older people, Parkinson’s disease is a growing health threat to our ever-aging population. Despite remarkable advances in our understanding of this disease, all therapeutics currently available only act to improve symptoms but cannot stop the disease progression. Therefore, it is essential that more effective drug discovery methods and approaches are developed, validated, and used for the discovery of disease-modifying treatments for Parkinson’s disease. Drug repurposing, also known as drug repositioning, or the process of finding new uses for existing or abandoned pharmaceuticals, has been recognized as a cost-effective and timeefficient way to develop new drugs, being equally promising as de novo drug discovery in the field of neurodegeneration and, more specifically for Parkinson’s disease. The availability of several established libraries of clinical drugs and fast evolvement in disease biology, genomics and bioinformatics has stimulated the momentums of both in silico and activity-based drug repurposing. With the successful clinical introduction of several repurposed drugs for Parkinson’s disease, drug repurposing has now become a robust alternative approach to the discovery and development of novel drugs for this disease. In this review, recent advances in drug repurposing for Parkinson’s disease will be discussed.

Decoding Protein-protein Interactions: An Overview

2020 ◽  
Vol 20 (10) ◽  
pp. 855-882
Author(s):  
Olivia Slater ◽  
Bethany Miller ◽  
Maria Kontoyianni
Keyword(s):  
Drug Discovery ◽  
Protein Interactions ◽  
Drug Repurposing ◽  
Protein Docking ◽  
Target Space ◽  
Protein Protein Interactions ◽  
X Ray Crystallography ◽  
Protein Protein Interaction ◽  
Interaction Sites ◽  
Long Time

Drug discovery has focused on the paradigm “one drug, one target” for a long time. However, small molecules can act at multiple macromolecular targets, which serves as the basis for drug repurposing. In an effort to expand the target space, and given advances in X-ray crystallography, protein-protein interactions have become an emerging focus area of drug discovery enterprises. Proteins interact with other biomolecules and it is this intricate network of interactions that determines the behavior of the system and its biological processes. In this review, we briefly discuss networks in disease, followed by computational methods for protein-protein complex prediction. Computational methodologies and techniques employed towards objectives such as protein-protein docking, protein-protein interactions, and interface predictions are described extensively. Docking aims at producing a complex between proteins, while interface predictions identify a subset of residues on one protein that could interact with a partner, and protein-protein interaction sites address whether two proteins interact. In addition, approaches to predict hot spots and binding sites are presented along with a representative example of our internal project on the chemokine CXC receptor 3 B-isoform and predictive modeling with IP10 and PF4.

The Drug Factory: Industrializing How New Drugs Are Found

2021 ◽  
pp. 247255522110281
Author(s):  
August Allen ◽  
Lina Nilsson
Keyword(s):  
Machine Learning ◽  
Drug Discovery ◽  
Feedback Loops ◽  
New Drugs

In this perspective, the authors paint a vision for industrializing drug discovery with an “atoms and bits” approach. This approach leverages advancements in machine learning, automation, and biological tools to create a platform for drug discovery that de-specializes the output of insights and generates feedback loops to iterate on each success and failure. Recursion Pharmaceuticals, where the authors work, is provided as an example of how one company is attempting to achieve this vision.

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