scholarly journals MmpL3 Inhibition: A New Approach to Treat Nontuberculous Mycobacterial Infections

2020 ◽  
Vol 21 (17) ◽  
pp. 6202
Author(s):  
Jigar P. Sethiya ◽  
Melanie A. Sowards ◽  
Mary Jackson ◽  
Elton Jeffrey North
Keyword(s):  
Adverse Reactions ◽  
Nontuberculous Mycobacteria ◽  
Mycobacterium Leprae ◽  
Mandatory Reporting ◽  
New Approach ◽  
Mycolic Acids ◽  
Drug Candidates ◽  
Environmental Mycobacteria ◽  
Antimycobacterial Agents ◽  
Current Therapies

Outside of Mycobacterium tuberculosis and Mycobacterium leprae, nontuberculous mycobacteria (NTM) are environmental mycobacteria (>190 species) and are classified as slow- or rapid-growing mycobacteria. Infections caused by NTM show an increased incidence in immunocompromised patients and patients with underlying structural lung disease. The true global prevalence of NTM infections remains unknown because many countries do not require mandatory reporting of the infection. This is coupled with a challenging diagnosis and identification of the species. Current therapies for treatment of NTM infections require multidrug regimens for a minimum of 18 months and are associated with serious adverse reactions, infection relapse, and high reinfection rates, necessitating discovery of novel antimycobacterial agents. Robust drug discovery processes have discovered inhibitors targeting mycobacterial membrane protein large 3 (MmpL3), a protein responsible for translocating mycolic acids from the inner membrane to periplasm in the biosynthesis of the mycobacterial cell membrane. This review focuses on promising new chemical scaffolds that inhibit MmpL3 function and represent interesting and promising putative drug candidates for the treatment of NTM infections. Additionally, agents (FS-1, SMARt-420, C10) that promote reversion of drug resistance are also reviewed.

scholarly journals The Antimalarial Mefloquine Shows Activity against Mycobacterium abscessus, Inhibiting Mycolic Acid Metabolism

2021 ◽  
Vol 22 (16) ◽  
pp. 8533
Author(s):  
Giulia Degiacomi ◽  
Laurent Roberto Chiarelli ◽  
Deborah Recchia ◽  
Elena Petricci ◽  
Beatrice Gianibbi ◽  
...  
Keyword(s):  
Acid Metabolism ◽  
Three Dimensional ◽  
Mycolic Acid ◽  
Mycobacterium Abscessus ◽  
Opportunistic Pathogens ◽  
Mycolic Acids ◽  
Drug Candidates ◽  
Antimycobacterial Agents ◽  
New Compounds ◽  
Novel Drug

Some nontuberculous mycobacteria (NTM) are considered opportunistic pathogens. Nevertheless, NTM infections are increasing worldwide, becoming a major public health threat. Furthermore, there is no current specific drugs to treat these infections, and the recommended regimens generally lack efficacy, emphasizing the need for novel antibacterial compounds. In this paper, we focused on the essential mycolic acids transporter MmpL3, which is a well-characterized target of several antimycobacterial agents, to identify new compounds active against Mycobacterium abscessus (Mab). From the crystal structure of MmpL3 in complex with known inhibitors, through an in silico approach, we developed a pharmacophore that was used as a three-dimensional filter to identify new putative MmpL3 ligands within databases of known drugs. Among the prioritized compounds, mefloquine showed appreciable activity against Mab (MIC = 16 μg/mL). The compound was confirmed to interfere with mycolic acids biosynthesis, and proved to also be active against other NTMs, including drug-resistant clinical isolates. Importantly, mefloquine is a well-known antimalarial agent, opening the possibility of repurposing an already approved drug, which is a useful strategy to reduce the time and cost of disclosing novel drug candidates.

scholarly journals Nontuberculous mycobacteria in hospital water systems: application of HPLC for identification of environmental mycobacteria

2003 ◽  
Vol 1 (3) ◽  
pp. 133-139 ◽  
Author(s):  
L. Galassi ◽  
R. Donato ◽  
E. Tortoli ◽  
D. Burrini ◽  
D. Santianni ◽  
...  
Keyword(s):  
High Performance ◽  
Nontuberculous Mycobacteria ◽  
Water System ◽  
Water Systems ◽  
Mycobacterium Fortuitum ◽  
Mycolic Acids ◽  
Environmental Mycobacteria ◽  
First Choice ◽  
One Year ◽  
Choice Method

Nontuberculous mycobacteria (NTM), ubiquitous in water environments, are increasingly recognized as nosocomial pathogens. Our study reports a one-year survey of the water system of two hospitals, A and B, in a small town near Florence, Italy. NTM were found throughout the study period in both settings, but B showed a significantly higher mycobacterial load. Mycobacterium gordonae and Mycobacterium fortuitum were the most frequent species isolated. Identification was carried out by conventional techniques and by high performance liquid chromatography (HPLC) analysis of cell wall mycolic acids. HPLC profiling could be used as a first-choice method for identification of environmental mycobacteria.

Click Reactions in Chemistry of Triterpenes - Advances Towards Development of Potential Therapeutics

2018 ◽  
Vol 25 (5) ◽  
pp. 636-658 ◽  
Author(s):  
Jan Pokorny ◽  
Lucie Borkova ◽  
Milan Urban
Keyword(s):  
Biological Activities ◽  
Synthetic Approach ◽  
Clinical Use ◽  
New Approach ◽  
Click Reactions ◽  
Drug Candidates ◽  
The Past ◽  
Low Toxicity ◽  
New Compounds ◽  
Potential Therapeutics

Triterpenoids are natural compounds with a large variety of biological activities such as anticancer, antiviral, antibacterial, antifungal, antiparazitic, antiinflammatory and others. Despite their low toxicity and simple availability from the natural resources, their clinical use is still severely limited by their higher IC50 and worse pharmacological properties than in the currently used therapeutics. This fact encouraged a number of researchers to develop new terpenic derivatives more suitable for the potential clinical use. This review summarizes a new approach to improve both, the activity and ADME-Tox properties by connecting active terpenes to another modifying molecules using click reactions. Within the past few years, this synthetic approach was well explored yielding a lot of great improvements of the parent compounds along with some less successful attempts. A large quantity of the new compounds presented here are superior in both activity and ADME-Tox properties to their parents. This review should serve the researchers who need to promote their hit triterpenic structures towards their clinical use and it is intended as a guide for the chemical synthesis of better drug candidates.

Privileged Structures in the Design of Potential Drug Candidates for Neglected Diseases

2019 ◽  
Vol 26 (23) ◽  
pp. 4323-4354 ◽  
Author(s):  
Ana Cristina Lima Leite ◽  
José Wanderlan Pontes Espíndola ◽  
Marcos Veríssimo de Oliveira Cardoso ◽  
Gevanio Bezerra de Oliveira Filho
Keyword(s):  
Biologically Active ◽  
Neglected Diseases ◽  
Financial Return ◽  
Drug Candidates ◽  
Lead Compounds ◽  
Wide Range ◽  
Methods Of Synthesis ◽  
Current Therapies ◽  
Resistant Strains ◽  
Privileged Structures

Background: Privileged motifs are recurring in a wide range of biologically active compounds that reach different pharmaceutical targets and pathways and could represent a suitable start point to access potential candidates in the neglected diseases field. The current therapies to treat these diseases are based in drugs that lack of the desired effectiveness, affordable methods of synthesis and allow a way to emergence of resistant strains. Due the lack of financial return, only few pharmaceutical companies have been investing in research for new therapeutics for neglected diseases (ND). Methods: Based on the literature search from 2002 to 2016, we discuss how six privileged motifs, focusing phthalimide, isatin, indole, thiosemicarbazone, thiazole, and thiazolidinone are particularly recurrent in compounds active against some of neglected diseases. Results: It was observed that attention was paid particularly for Chagas disease, malaria, tuberculosis, schistosomiasis, leishmaniasis, dengue, African sleeping sickness (Human African Trypanosomiasis - HAT) and toxoplasmosis. It was possible to verify that, among the ND, antitrypanosomal and antiplasmodial activities were between the most searched. Besides, thiosemicarbazone moiety seems to be the most versatile and frequently explored scaffold. As well, phthalimide, isatin, thiazole, and thiazolidone nucleus have been also explored in the ND field. Conclusion: Some described compounds, appear to be promising drug candidates, while others could represent a valuable inspiration in the research for new lead compounds.

scholarly journals Molecular Hybridization as a Tool in the Design of Multi-target Directed Drug Candidates for Neurodegenerative Diseases

2020 ◽  
Vol 18 (5) ◽  
pp. 348-407 ◽  
Author(s):  
Vanessa Silva Gontijo ◽  
Flávia P. Dias Viegas ◽  
Cindy Juliet Cristancho Ortiz ◽  
Matheus de Freitas Silva ◽  
Caio Miranda Damasio ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Rational Design ◽  
Brain Regions ◽  
Molecular Hybridization ◽  
Drug Candidate ◽  
New Paradigm ◽  
New Approach ◽  
Biological Targets ◽  
Drug Candidates ◽  
Biochemical Pathways

Neurodegenerative Diseases (NDs) are progressive multifactorial neurological pathologies related to neuronal impairment and functional loss from different brain regions. Currently, no effective treatments are available for any NDs, and this lack of efficacy has been attributed to the multitude of interconnected factors involved in their pathophysiology. In the last two decades, a new approach for the rational design of new drug candidates, also called multitarget-directed ligands (MTDLs) strategy, has emerged and has been used in the design and for the development of a variety of hybrid compounds capable to act simultaneously in diverse biological targets. Based on the polypharmacology concept, this new paradigm has been thought as a more secure and effective way for modulating concomitantly two or more biochemical pathways responsible for the onset and progress of NDs, trying to overcome low therapeutical effectiveness. As a complement to our previous review article (Curr. Med. Chem. 2007, 14 (17), 1829-1852. https://doi.org/10.2174/092986707781058805), herein we aimed to cover the period from 2008 to 2019 and highlight the most recent advances of the exploitation of Molecular Hybridization (MH) as a tool in the rational design of innovative multifunctional drug candidate prototypes for the treatment of NDs, specially focused on AD, PD, HD and ALS.

Infections due to Mycobacterium leprae and Nontuberculous Mycobacteria

2011 ◽  
Author(s):  
Michael K Leonard Jr ◽  
Henry M Blumberg ◽  
Carlos Franco-Paredes
Keyword(s):  
Nontuberculous Mycobacteria ◽  
Clinical Manifestations ◽  
Mycobacterium Leprae ◽  
Lepromatous Leprosy ◽  
Molecular Diagnostic ◽  
Diagnostic Tools ◽  
Human Pathogens ◽  
Mycobacterial Infections ◽  
Rapidly Growing Mycobacteria ◽  
Treatment Regimens

Mycobacterium leprae infection (i.e., leprosy) is a disease that has been recognized—and often misunderstood—since ancient times. The emergence of HIV/AIDS and the development of newer culture methodologies and molecular diagnostic tools have brought about increased interest in the epidemiology, diagnosis, and treatment of human infections from nontuberculous mycobacteria (NTM). More than 140 species of NTM have been identified; approximately 50 of these may be pathogenic for humans, causing a broad spectrum of disease. This chapter covers both M. leprae and selected NTM organisms, including M. avium complex; M. kansasii; M. marinum; and rapidly growing mycobacteria such as M. chelonae, M. fortuitum, and M. abscessus. The section on leprosy encompasses subsections on diagnosis, clinical manifestations and classification, laboratory studies, treatment, and leprosy reactions. Treatments for nontuberculous mycobacteria infections are also covered. Figures include a natural history of leprosy, tuberculoid leprosy, lepromatous leprosy, and various forms of borderline leprosy, as well as type 1 and type 2 leprosy reaction. Tables include the Ridley-Jopling classification of leprosy, recommendations for treatment of leprosy, clinical characteristics and treatment of leprosy, major clinical syndromes associated with nontuberculous mycobacterial infections, diagnosing nontuberculous mycobacterial lung disease, a listing of slow and rapidly growing mycobacteria that are human pathogens, plus treatment regimens for selected nontuberculous mycobacterial infections in adults. This review contains 59 references.

scholarly journals Hepatocyte-based flow analytical bioreactor for online xenobiotics metabolism bioprediction

2017 ◽  
Vol 4 ◽  
pp. 184954351770289
Author(s):  
M Helvenstein ◽  
S Hambÿe ◽  
B Blankert
Keyword(s):  
Iron Oxide ◽  
Iron Oxide Nanoparticles ◽  
High Performance ◽  
Screening Tools ◽  
Oxide Nanoparticles ◽  
New Approach ◽  
Drug Candidates ◽  
Magnetically Trapped ◽  
Major Interest

The research for new in vitro screening tools for predictive metabolic profiling of drug candidates is of major interest in the pharmaceutical field. The main motivation is to avoid late rejection in drug development and to deliver safer drugs to the market. Thanks to the superparamagnetic properties of iron oxide nanoparticles, a flow bioreactor has been developed which is able to perform xenobiotic metabolism studies. The selected cell line (HepaRG) maintained its metabolic competencies once iron oxide nanoparticles were internalized. Based on magnetically trapped cells in a homemade immobilization chamber, through which a flow of circulating phase was injected to transport nutrients and/or the studied xenobiotic, off-line and online (when coupled to a high-performance liquid chromatography chain) metabolic assays were developed using diclofenac as a reference compound. The diclofenac demonstrated a similar metabolization profile chromatogram, both with the newly developed setup and with the control situation. Highly versatile, this pioneering and innovative instrumental design paves the way for a new approach in predictive metabolism studies.

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