Two for the price of one: attacking the energetic-metabolic hub of mycobacteria to produce new chemotherapeutic agents

Publication date: Available online 13 November 2019Source: Progress in Biophysics and Molecular BiologyAuthor(s): Kiel Hards, Cara Adolph, Liam K. Harold, Matthew B. McNeil, Chen-Yi Cheung, Adrian Jinich, Kyu Y. Rhee, Gregory M. CookAbstractCellular bioenergetics is an area showing promise for the development of new antimicrobials, antimalarials and cancer therapy. Enzymes involved in central carbon metabolism and energy generation are essential mediators of bacterial physiology, persistence and pathogenicity, lending themselves natural interest for drug discovery. In particular, succinate and malate are two major focal points in both the central carbon metabolism and the respiratory chain of Mycobacterium tuberculosis. Both serve as direct links between the citric acid cycle and the respiratory chain due to the quinone-linked reactions of succinate dehydrogenase, fumarate reductase and malate:quinone oxidoreductase. Inhibitors against these enzymes therefore hold the promise of disrupting two distinct, but essential, cellular processes at the same time. In this review, we discuss the roles and unique adaptations of these enzymes and critically evaluate the role that future inhibitors of these complexes could play in the bioenergetics target space.
Source: Progress in Biophysics and Molecular Biology - Category: Molecular Biology Source Type: research

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Lung carcinoma therapy using epidermal growth factor receptor‑targeted lipid polymeric nanoparticles co‑loaded with cisplatin and doxorubicin. Oncol Rep. 2019 Sep 18;: Authors: Nan Y Abstract The rate of lung cancer in tuberculosis (TB) patients is 7 to 30% higher than that in healthy individuals. Conventional chemotherapy of lung cancer shows limited efficiency due to poor tumor tissue drug accumulation and nonspecific cytotoxicity. Epidermal growth factor receptor (EGFR) is a promising target, which is overexpressed in lung carcinomas. In the present study, EGFR‑targeted nanopart...
Source: Oncology Reports - Category: Cancer & Oncology Tags: Oncol Rep Source Type: research
In this study, we found that cofilin competes with tau for direct microtubule binding in vitro, in cells, and in vivo, which inhibits tau-induced microtubule assembly. Genetic reduction of cofilin mitigates tauopathy and synaptic defects in Tau-P301S mice and movement deficits in tau transgenic C. elegans. The pathogenic effects of cofilin are selectively mediated by activated cofilin, as active but not inactive cofilin selectively interacts with tubulin, destabilizes microtubules, and promotes tauopathy. These results therefore indicate that activated cofilin plays an essential intermediary role in neurotoxic signaling th...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
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Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
We report here that the maximum analgesic effect of mycolactone was observed at a time post-injection, when mycolactone amounts remaining in the tissue were very low nonetheless similar to the ones obtained in oedematous tissues of mice infected with M. ulcerans. Materials and Methods Animal Experimentation All animal experiments were performed in accordance with national (articles R214-87 to R214-90 from the French “rural code”) and European guidelines (directive 2010/63/EU of the European Parliament and of the Council of September 22, 2010 on the protection of animals used for scientific purposes). All pro...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research
Mariana Girão1,2, Inês Ribeiro1, Tiago Ribeiro1, Isabel C. Azevedo1, Filipe Pereira1, Ralph Urbatzka1, Pedro N. Leão1 and Maria F. Carvalho1* 1Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Porto, Portugal 2Department of Biology, Faculty of Sciences, University of Porto, Porto, Portugal Nature is the major reservoir of biologically active molecules. The urgent need of finding novel molecules for pharmaceutical application is prompting the research of underexplored environments, such as marine ecosystems. Here, we investigated cultivable actinobacteria asso...
Source: Frontiers in Microbiology - Category: Microbiology Source Type: research
Purpose of review In the light of poor management outcomes of antibiotic-resistant respiratory tract infection (RTI)-associated sepsis syndrome and multidrug-resistant tuberculosis (MDR-TB), new management interventions based on host-directed therapies (HDTs) are warranted to improve morbidity, mortality and long-term functional outcomes. We review developments in potential HDTs based on precision cancer therapy concepts applicable to RTIs including MDR-TB. Recent findings Immune reactivity, tissue destruction and repair processes identified during studies of cancer immunotherapy share common pathogenetic mechanisms w...
Source: Current Opinion in Pulmonary Medicine - Category: Respiratory Medicine Tags: INFECTIOUS DISEASES: Edited by Michael S. Niederman and Alimuddin Zumla Source Type: research
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Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
Intravesical instillation of Bacillus Calmette –Guérin (BCG) has been a first-line therapy for non-muscle invasive bladder cancer for the last four decades. However, this treatment causes serious adverse events in a significant number of patients and a substantial percentage of recurrence episodes. MTBVAC is a live attenuated vaccine derived from a Mycobacterium tuberculosis clinical isolate and is currently under evaluation in clinical trials to replace BCG as a tuberculosis vaccine. Here, we describe for the first time the potential of MTBVAC as a bladder cancer therapy in vitro and in vivo in a preclinical model.
Source: Translational Research - Category: Research Authors: Source Type: research
Intravesical instillation of bacillus Calmette-Gu érin (BCG) has been a first-line therapy for non–muscle-invasive bladder cancer for the last 4 decades. However, this treatment causes serious adverse events in a significant number of patients and a substantial percentage of recurrence episodes. MTBVAC is a live-attenuated vaccine derived from a Mycobacterium tuberculosis clinical isolate and is currently under evaluation in clinical trials to replace BCG as a tuberculosis vaccine. Here, we describe for the first time the potential of MTBVAC as a bladder cancer therapy in vitro and in vivo in a preclinical model.
Source: Translational Research - Category: Research Authors: Source Type: research
ute;n C, Aguilo N Abstract Intravesical instillation of bacillus Calmette-Guérin (BCG) has been a first-line therapy for non-muscle-invasive bladder cancer for the last 4 decades. However, this treatment causes serious adverse events in a significant number of patients and a substantial percentage of recurrence episodes. MTBVAC is a live-attenuated vaccine derived from a Mycobacterium tuberculosis clinical isolate and is currently under evaluation in clinical trials to replace BCG as a tuberculosis vaccine. Here, we describe for the first time the potential of MTBVAC as a bladder cancer therapy in vitro and...
Source: Translational Research : the journal of laboratory and clinical medicine - Category: Laboratory Medicine Authors: Tags: Transl Res Source Type: research
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