Hybridization approach to drug discovery inhibiting Mycobacterium tuberculosis. An overview.

2020 ◽  
Vol 20 ◽  
Author(s):  
Daniele Zampieri ◽  
Maria G. Mamolo
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Discovery ◽  
Cause Of Death ◽  
Medicinal Chemistry ◽  
Causes Of Death ◽  
Infectious Agent ◽  
Drug Resistant ◽  
New Chemical Entities ◽  
Hybrid Ligands

: Tuberculosis is one of the top 10 causes of death worldwide and the leading cause of death from a single infectious agent mainly due to Mycobacterium tuberculosis (MTB). Recently, clinical prognoses have worsened due to the emergence of multi-drug resistant (MDR) and extensive-drug resistant (XDR) tuberculosis which lead to the need of new, efficient and safely drugs. Among the several strategies, polypharmacology could be considered one of the best solutions, in particular the multi-target directed ligands strategy (MTDLs), based on the synthesis of hybrid ligands acting against two targets of the pathogen. The framework strategy comprises linking, fusing and merging approaches to develop new chemical entities. With these premises, this review aims to provide an overview of recent hybridization approach, in medicinal chemistry, of the most recent and promising multitargeting antimycobacterial candidates.

scholarly journals 5 New guidelines for managing tuberculosis

2019 ◽  
Vol 95 (1130) ◽  
pp. 686.2-686
Author(s):  
Paul Nunn
Keyword(s):  
Causes Of Death ◽  
Meta Analysis ◽  
Infectious Agent ◽  
Drug Resistant ◽  
New Agents ◽  
Pulmonary Tb ◽  
Effectiveness Analysis ◽  
Mdr Tb ◽  
New Guidelines ◽  
The Uk

In 2018, tuberculosis (TB) was still among the top 10 leading causes of death, and the leading infectious agent, above HIV/AIDS. An estimated 10 million cases occurred in 2018, with 1.2 million deaths in people uninfected with HIV, and another 250,000 cases of HIV-associated TB. Among all TB cases, 8–6% were HIV infected; 57% were men, 32% women and 11% children (<15 years). About 500,000 cases of rifampicin resistant RR-TB also occurred. Between 2000 and 2018 TB incidence fell on average about 1.6% annually, and 2% between 2017 and 2018. The new global control targets will be presented and recent changes to guidelines positioned in this new scenario.Guidelines for TB management from the UK, US and WHO were reviewed for recent changes. NICE’s 2016 guidance not to screen contacts of non-pulmonary TB met with widespread criticism, but has recently been supported by a cost-effectiveness analysis. A 2019 meta-analysis of the seminal 2014 studies, OFLOTUB, ReMOX and RIFAQUIN trials showed that while none of those trials showed non-inferiority of a four month fluoroquinolone-containing regimen in all patients, those with low smear grade or no cavitation may be treated with 4-month rifampicin containing regimens. ATS/CDC/IDSA guidelines reflect this, but had not been accepted in the UK by October 2019. WHO has recently recommended the use of new agents in the treatment of rifampicin and multi-drug resistant TB. The rapidly-evolving picture of treatment recommendations for MDR-TB will be explained.

scholarly journals Vacuna contra la tuberculosis BCG: Eficacia y efectos adversos / BCG vaccine against tuberculosis: Efficacy and adverse effects

Ciencia Unemi ◽  
2015 ◽  
Vol 8 (16) ◽  
pp. 120
Author(s):  
Steven Quezada Andrade ◽  
Sunny Sanchez Giler
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Adverse Effects ◽  
Cause Of Death ◽  
Infectious Agent ◽  
Bcg Vaccine ◽  
Current Status ◽  
Infected Person ◽  
Bacillus Calmette Guerin ◽  
Related Factors ◽  
Research Population

Originada por el Mycobacterium tuberculosis. Esto llevó a la creación de una vacuna que se presentó oficialmente en 1924 y que se conoce como Bacilo Calmette y Guerin (BCG), desde entonces se la ha utilizado. Sin embargo, ha habido numerosas investigaciones sobre su eficacia y otros factores relacionados que han mostrado desequilibrio. Varios países recomiendan el uso de esta vacuna en los recién nacidos, pero en el caso de Ecuador se ha dejado de recomendar su aplicación, a pesar de que no existan datos en relación a la eficacia de la vacuna en dicho país. Otros estudios demuestran que el conocimiento de las personas acerca de la enfermedad es muy pobre, permitiendo así que esta pueda propagarse con mayor facilidad, debido a que la persona infectada no conoce el tipo de sintomatología que la Tuberculosis genera. Este artículo tiene el objetivo de conocer el estado actual de la eficiencia y seguridad de la BCG mediante la revisión y análisis de artículos recopilados relacionados al uso de la vacuna y su eficacia en la población investigada. AbstractTB is the second leading cause of death from an infectious agent, disease caused by Mycobacterium tuberculosis. It allowed the creation of a vaccine officially launched in 1924 and known as Bacillus Calmette-Guerin (BCG) used since then. However, there has been extensive research on its effectiveness and other related factors have shown an imbalance. Several countries recommend the use of this vaccine in infants, but in the case of Ecuador has failed to suggest its application, although there are no data regarding the efficacy of the vaccine in that country. Other studies show that the knowledge of people about the disease is destitute, thus allowing this could spread more quickly because the infected person does not know the type of symptoms that generates Tuberculosis. This article aims to identify the current status of the efficiency and safety of BCG through review and analysis of collected items related to the use of the vaccine and its effectiveness in the research population.

scholarly journals Activity of Semi-Synthetic Mulinanes against MDR, Pre-XDR, and XDR Strains of Mycobacterium tuberculosis

Metabolites ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 876
Author(s):  
María Alejandrina Martínez-González ◽  
Luis Manuel Peña-Rodríguez ◽  
Andrés Humberto Uc-Cachón ◽  
Jorge Bórquez ◽  
Mario J. Simirgiotis ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Infectious Agent ◽  
Vero Cells ◽  
Bactericidal Effect ◽  
Multidrug Resistant ◽  
New Drugs ◽  
Drug Resistant ◽  
Adjuvant Effect ◽  
Extensively Drug Resistant

Tuberculosis causes more than 1.2 million deaths each year. Worldwide, it is the first cause of death by a single infectious agent. The emergence of drug-resistant strains has limited pharmacological treatment of the disease and today, new drugs are urgently needed. Semi-synthetic mulinanes have previously shown important activity against multidrug-resistant (MDR) Mycobacterium tuberculosis. In this investigation, a new set of semi-synthetic mulinanes were synthetized, characterized, and evaluated for their in vitro activity against three drug-resistant clinical isolates of M. tuberculosis: MDR, pre-extensively Drug-Resistant (pre-XDR), and extensively Drug-Resistant (XDR), and against the drug-susceptible laboratory reference strain H37Rv. Derivative 1a showed the best anti-TB activity (minimum inhibitory concentration [MIC] = 5.4 µM) against the susceptible strain and was twice as potent (MIC = 2.7 µM) on the MDR, pre-XDR, and XDR strains and also possessed a bactericidal effect. Derivative 1a was also tested for its anti-TB activity in mice infected with the MDR strain. In this case, 1a produced a significant reduction of pulmonary bacilli loads, six times lower than the control, when tested at 0.2536 mg/Kg. In addition, 1a demonstrated an adjuvant effect by shortening second-line chemotherapy. Finally, the selectivity index of >15.64 shown by 1a when tested on Vero cells makes this derivative an important candidate for future studies in the development of novel antitubercular agents.

scholarly journals New Isoniazid Complexes, Promising Agents Against Mycobacterium tuberculosis

2017 ◽  
Vol 57 (3) ◽  
Author(s):  
Mariana Poggi ◽  
Rafael Barroso ◽  
Antonio José Costa-Filho ◽  
Heloisa Barbosa de Barros ◽  
Fernando Pavan ◽  
...  
Keyword(s):  
Public Health ◽  
Mycobacterium Tuberculosis ◽  
Drug Discovery ◽  
Cobalt Complexes ◽  
Selectivity Index ◽  
Synthesis And Characterization ◽  
Drug Resistant ◽  
Critical Situation ◽  
Research Priority ◽  
Microbial Strains

Tuberculosis (TB) is a public health disease that produces several million deaths annually worldwide. Due to this critical situation and the appearance of drug-resistant microbial strains, innovation in TB drug discovery is a research priority. In this work, the synthesis and characterization by elemental analysis, hermogravimetry, conductimetric measurements and spectroscopies UV-Vis, IR and EPR of [Cu(INH)(H<sub>2</sub>O)]SO<sub>4</sub>⋅2H<sub>2</sub>O (Cu-INH) and [CoCl(INH)<sub>2</sub>(H<sub>2</sub>O)] Cl⋅2.5H<sub>2</sub>O (Co-INH) complexes with isoniazid (INH) are reported. Besides, the lipophilicity, the activity against <em>Mycobacterium tuberculosis</em> (MIC<sub>Cu-INH</sub> = 0.78 μg/mL and MIC<sub>Co-INH</sub> = 0.19 μg/mL) and the cytotoxicity (IC<sub>50</sub> = 48.8 and 625 μg/mL for the copper and cobalt complexes, respectively) were measured and the selectivity index (62.5 for Cu-INH and 3205 for Co-INH) was calculated. These results indicate that these complexes are good candidates for further studies.

scholarly journals Lung Epithelial Signaling Mediates Early Vaccine-Induced CD4 + T Cell Activation and Mycobacterium tuberculosis Control

mBio ◽  
2021 ◽  
Author(s):  
Shibali Das ◽  
Nancy D. Marin ◽  
Ekaterina Esaulova ◽  
Mushtaq Ahmed ◽  
Amanda Swain ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Cause Of Death ◽  
T Cell Activation ◽  
Cell Activation ◽  
Infectious Agent ◽  
Cd4 T Cell ◽  
Tuberculosis Control ◽  
Lung Epithelial

Tuberculosis is a leading cause of death due to single infectious agent accounting 1.4 million deaths each year. The only licensed vaccine, BCG, is not effective due to variable efficacy.

scholarly journals Editorial on Special Issue “Tuberculosis Drug Discovery and Development 2019”

2020 ◽  
Vol 10 (17) ◽  
pp. 6069
Author(s):  
Claudia Sala ◽  
Laurent Roberto Chiarelli ◽  
Giovanna Riccardi
Keyword(s):  
Infectious Disease ◽  
Mycobacterium Tuberculosis ◽  
Drug Discovery ◽  
Human Health ◽  
Cause Of Death ◽  
Etiological Agent ◽  
Special Issue ◽  
Drug Discovery And Development ◽  
Global Challenge

Mycobacterium tuberculosis, the etiological agent of human tuberculosis (TB), represents a global challenge to human health since it is the main cause of death by an infectious disease worldwide [...]

scholarly journals Systematic review protocol on Bacillus Calmette-Guerin (BCG) revaccination and protection against tuberculosis

BMJ Open ◽  
2019 ◽  
Vol 9 (10) ◽  
pp. e027033 ◽  
Author(s):  
Phetole Walter Mahasha ◽  
Duduzile Edith Ndwandwe ◽  
Edison Johannes Mavundza ◽  
Muki Shey ◽  
Charles Shey Wiysonge
Keyword(s):  
Systematic Review ◽  
Mycobacterium Tuberculosis ◽  
Cause Of Death ◽  
Systematic Reviews ◽  
Evaluation Method ◽  
Infectious Agent ◽  
Cochrane Central Register ◽  
Recent Trial ◽  
Assessment Development ◽  
Ethical Approval

IntroductionTuberculosis (TB) is a disease caused byMycobacterium tuberculosis(M.TB) and other species of the Mycobacterium tuberculosis complex. Globally, TB is ranked as the ninth leading cause of death and the leading cause of death from a single infectious agent. The bacille Calmette-Guerin (BCG) vaccine has been used globally since 1921 for the prevention of TB in humans, and was derived from an attenuated strain ofMycobacterium bovis. Evidence from previous randomised trials show that the efficacy of primary BCG vaccination against pulmonary TB ranged from no protection to very high protection. In addition, some studies suggest a benefit of BCG revaccination. For example, a recent trial conducted in South Africa showed that BCG revaccination of adolescents could reduce the risk of TB infection by half. However, we are not aware of any recent systematic reviews of the effects of BCG revaccination. Thus, the need for this systematic review of the effects of BCG revaccination on protection against TB infection and disease.Method and analysisWe will search PubMed, the Cochrane Central Register of Controlled Trials, EMBASE, WHO International Clinical Trials Registry Platform and reference lists of relevant publications for potentially eligible studies. We will screen search outputs, select eligible studies, extract data and assess risk of bias in duplicate. Discrepancies will be resolved by discussion and consensus or arbitration. We will use the Grading of Recommendations Assessment, Development and Evaluation method to assess the certainty of the evidence. The planned systematic review was registered with the International Prospective Register of Systematic Reviews (PROSPERO) in August 2018.Ethics and disseminationPublicly available data will be used, hence no formal ethical approval will be required for this review. The findings of the review will be disseminated through conference presentations and publication in an open-access peer-reviewed journal.PROSPERO registration numberCRD42018105916

scholarly journals Developing synergistic drug combinations to restore antibiotic sensitivity in drug-resistant Mycobacterium tuberculosis

2019 ◽  
Author(s):  
Charles Omollo ◽  
Vinayak Singh ◽  
Elizabeth Kigondu ◽  
Antonina Wasuna ◽  
Pooja Agarwal ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Efflux Pump ◽  
Ex Vivo ◽  
Genetic Resistance ◽  
Antibiotic Sensitivity ◽  
Infectious Agent ◽  
Drug Combinations ◽  
Major Facilitator Superfamily ◽  
Drug Resistant

ABSTRACTTuberculosis (TB) is a leading global cause of mortality owing to an infectious agent, accounting for almost one-third of antimicrobial resistance (AMR) deaths annually. We aimed to identify synergistic anti-TB drug combinations with the capacity to restore therapeutic efficacy against drug-resistant mutants of the causative agent, Mycobacterium tuberculosis. We investigated combinations containing the known translational inhibitors, spectinomycin (SPT) and fusidic acid (FA), or the phenothiazine, chlorpromazine (CPZ), which disrupts mycobacterial energy metabolism. Potentiation of whole-cell drug efficacy was observed in SPT-CPZ combinations. This effect was lost against an M. tuberculosis mutant lacking the major facilitator superfamily (MFS) efflux pump, Rv1258c. Notably, the SPT-CPZ combination restored SPT efficacy against an SPT-resistant mutant carrying a g1379t point mutation in rrs, encoding the mycobacterial 16S ribosomal RNA. Combinations of SPT with FA, which targets the mycobacterial elongation factor G, exhibited potentiating activity against wild-type M. tuberculosis. Moreover, this combination produced a marginal potentiating effect against both FA-monoresistant and SPT-monoresistant mutants. Finally, combining SPT with the frontline anti-TB agents, rifampicin (RIF) and isoniazid, resulted in enhanced activity in vitro and ex vivo against both drug-susceptible M. tuberculosis and a RIF-monoresistant rpoB S531L mutant.These results support the utility of novel potentiating drug combinations in restoring antibiotic susceptibility of M. tuberculosis strains carrying genetic resistance to any one of the partner compounds.

scholarly journals Developing Synergistic Drug Combinations To Restore Antibiotic Sensitivity in Drug-Resistant Mycobacterium tuberculosis

2021 ◽  
Vol 65 (5) ◽  
Author(s):  
Charles Omollo ◽  
Vinayak Singh ◽  
Elizabeth Kigondu ◽  
Antonina Wasuna ◽  
Pooja Agarwal ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Efflux Pump ◽  
Ex Vivo ◽  
Antibiotic Sensitivity ◽  
Infectious Agent ◽  
Drug Combinations ◽  
Major Facilitator Superfamily ◽  
Drug Resistant ◽  
Content Type

ABSTRACT Tuberculosis (TB) is a leading global cause of mortality owing to an infectious agent, accounting for almost one-third of antimicrobial resistance (AMR) deaths annually. We aimed to identify synergistic anti-TB drug combinations with the capacity to restore therapeutic efficacy against drug-resistant mutants of the causative agent, Mycobacterium tuberculosis. We investigated combinations containing the known translational inhibitors, spectinomycin (SPT) and fusidic acid (FA), or the phenothiazine, chlorpromazine (CPZ), which disrupts mycobacterial energy metabolism. Potentiation of whole-cell drug efficacy was observed in SPT-CPZ combinations. This effect was lost against an M. tuberculosis mutant lacking the major facilitator superfamily (MFS) efflux pump, Rv1258c. Notably, the SPT-CPZ combination partially restored SPT efficacy against an SPT-resistant mutant carrying a g1379t point mutation in rrs, encoding the mycobacterial 16S rRNA. Combinations of SPT with FA, which targets the mycobacterial elongation factor G, exhibited potentiating activity against wild-type M. tuberculosis. Moreover, this combination produced a modest potentiating effect against both FA-monoresistant and SPT-monoresistant mutants. Finally, combining SPT with the frontline anti-TB agents, rifampicin (RIF) and isoniazid, resulted in enhanced activity in vitro and ex vivo against both drug-susceptible M. tuberculosis and a RIF-monoresistant rpoB S531L mutant. These results support the utility of novel potentiating drug combinations in restoring antibiotic susceptibility of M. tuberculosis strains carrying genetic resistance to any one of the partner compounds.

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