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Pharmaceuticals
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Novel Insights into Tuberculosis Research and Drug Discovery
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Novel Insights into Tuberculosis Research and Drug Discovery

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (15 December 2023) | Viewed by 17944

Special Issue Editor

Dr. Luís Constantino

E-Mail Website
Guest Editor
Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal
Interests: Mycobacterium; tuberculosis

Special Issue Information

Dear Colleagues,

Decades ago, it was anticipated that at this point in time, powerful antibiotics developed during the second half of the 20th century would have successfully eradicated tuberculosis. Unfortunately, virulent and deadly new strains have evolved, and the current situation is out of control.

In recognition of this issue, and to emphasise the importance of tuberculosis research, the UN declared the eradication of the tuberculosis epidemic by 2030 one of its Sustainable Development Goals.

While this is a challenging objective, the current state of TB research is fascinating, and these are exciting times in which to contribute to the fight. Timely dissemination of research findings is unquestionably one of the most useful contributions that researchers can make to leverage their own discoveries.

This Special Issue will focus on novel insights into tuberculosis research and drug discovery. Authors are welcome to contribute original research articles and reviews concerning not only new drugs and their mechanisms of action, but also new developments on existing and repurposing molecules. Explorations of prodrugs, formulation innovations, and alternative routes of drug delivery that may improve the performance of existing drugs are also welcome.

The goal is to encourage the development of new, improved medications and advance the management of tuberculosis. We hope you can contribute to this objective.

Dr. Luís Constantino
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • tuberculosis
  • mycobacterium tuberculosis
  • drug target
  • antitubercular
  • prodrug
  • drug metabolism
  • drug delivery
  • antitubercular resistance
  • drug development
  • drug resistance

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Published Papers (7 papers)

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Research

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15 pages, 4245 KiB  
Article
Structure of a Cyclic Peptide as an Inhibitor of Mycobacterium tuberculosis Transcription: NMR and Molecular Dynamics Simulations
by Filia Stephanie, Usman Sumo Friend Tambunan, Krzysztof Kuczera and Teruna J. Siahaan
Pharmaceuticals 2024, 17(11), 1545; https://doi.org/10.3390/ph17111545 - 18 Nov 2024
Viewed by 411
Abstract
Background and Objectives: A novel antitubercular cyclic peptide, Cyclo(1,6)-Ac-CLYHFC-NH2, was designed to bind at the rifampicin (RIF) binding site on the RNA polymerase (RNAP) of Mycobacterium tuberculosis (MTB). This peptide inhibits RNA elongation in the MTB transcription initiation assay in the [...] Read more.
Background and Objectives: A novel antitubercular cyclic peptide, Cyclo(1,6)-Ac-CLYHFC-NH2, was designed to bind at the rifampicin (RIF) binding site on the RNA polymerase (RNAP) of Mycobacterium tuberculosis (MTB). This peptide inhibits RNA elongation in the MTB transcription initiation assay in the nanomolar range, which can halt the MTB transcription initiation complex, similar to RIF. Therefore, determining the solution conformation of this peptide is useful in improving the peptide’s binding affinity to the RNAP. Methods: Here, the solution structure of Cyclo(1,6)-Ac-CLYHFC-NH2 was determined by two-dimensional (2D) NMR experiments and NMR-restrained molecular dynamic (MD) simulations. Results: All protons of Cyclo(1,6)-Ac-CLYHFC-NH2 were assigned using TOCSY and NOE NMR spectroscopy. The NOE cross-peak intensities were used to calculate interproton distances within the peptide. The JNH-HCα coupling constants were used to determine the possible Phi angles within the peptide. The interproton distances and calculated Phi angles from NMR were used in NMR-restrained MD simulations. The NOE spectra showed NH-to-NH cross-peaks at Leu2-to-Tyr3 and Tyr3-to-His4, indicating a βI-turn formation at the Cys1-Leu2-Tyr3-His4 sequence. Conclusions: The NMR-restrained MD simulations showed several low-energy conformations that were congruent with the NMR data. Finally, the conformation of this peptide will be used to design derivatives that can better inhibit RNAP activity. Full article
(This article belongs to the Special Issue Novel Insights into Tuberculosis Research and Drug Discovery)
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11 pages, 2279 KiB  
Article
Structural Study of a New MbtI-Inhibitor Complex: Towards an Optimized Model for Structure-Based Drug Discovery
by Matteo Mori, Stefania Villa, Laurent R. Chiarelli, Fiorella Meneghetti and Marco Bellinzoni
Pharmaceuticals 2023, 16(11), 1559; https://doi.org/10.3390/ph16111559 - 3 Nov 2023
Cited by 2 | Viewed by 1594
Abstract
MbtI from Mycobacterium tuberculosis (Mtb) is a Mg2+-dependent salicylate synthase, belonging to the chorismate-utilizing enzyme (CUE) family. As a fundamental player in iron acquisition, MbtI promotes the survival and pathogenicity of Mtb in the infected host. Hence, it has [...] Read more.
MbtI from Mycobacterium tuberculosis (Mtb) is a Mg2+-dependent salicylate synthase, belonging to the chorismate-utilizing enzyme (CUE) family. As a fundamental player in iron acquisition, MbtI promotes the survival and pathogenicity of Mtb in the infected host. Hence, it has emerged in the last decade as an innovative, potential target for the anti-virulence therapy of tuberculosis. In this context, 5-phenylfuran-2-carboxylic acids have been identified as potent MbtI inhibitors. The first co-crystal structure of MbtI in complex with a member of this class was described in 2020, showing the enzyme adopting an open configuration. Due to the high mobility of the loop adjacent to the binding pocket, large portions of the amino acid chain were not defined in the electron density map, hindering computational efforts aimed at structure-driven ligand optimization. Herein, we report a new, high-resolution co-crystal structure of MbtI with a furan-based derivative, in which the closed configuration of the enzyme allowed tracing the entirety of the active site pocket in the presence of the bound inhibitor. Moreover, we describe a new crystal structure of MbtI in open conformation and in complex with the known inhibitor methyl-AMT, suggesting that in vitro potency is not related to the observed enzyme conformation. These findings will prove fundamental to enhance the potency of this series via rational structure-based drug-design approaches. Full article
(This article belongs to the Special Issue Novel Insights into Tuberculosis Research and Drug Discovery)
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Review

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19 pages, 9191 KiB  
Review
The Use of Viral Vectors for Gene Therapy and Vaccination in Tuberculosis
by Dulce Mata-Espinosa, Jacqueline V. Lara-Espinosa, Jorge Barrios-Payán and Rogelio Hernández-Pando
Pharmaceuticals 2023, 16(10), 1475; https://doi.org/10.3390/ph16101475 - 16 Oct 2023
Cited by 2 | Viewed by 2272
Abstract
Tuberculosis (TB), an infection caused by Mycobacterium tuberculosis (Mtb), is one of the primary causes of death globally. The treatment of TB is long and based on several drugs, producing problems in compliance and toxicity, increasing Mtb resistance to first-line antibiotics that [...] Read more.
Tuberculosis (TB), an infection caused by Mycobacterium tuberculosis (Mtb), is one of the primary causes of death globally. The treatment of TB is long and based on several drugs, producing problems in compliance and toxicity, increasing Mtb resistance to first-line antibiotics that result in multidrug-resistant TB and extensively drug-resistant TB. Thus, the need for new anti-TB treatments has increased. Here, we review some model strategies to study gene therapy based on the administration of a recombinant adenovirus that encodes diverse cytokines, such as IFNγ, IL12, GM/CSF, OPN, TNFα, and antimicrobial peptides to enhance the protective immune response against Mtb. These models include a model of progressive pulmonary TB, a model of chronic infection similar to latent TB, and a murine model of pulmonary Mtb transmission to close contacts. We also review new vaccines that deliver Mtb antigens via particle- or virus-based vectors and trigger protective immune responses. The results obtained in this type of research suggest that this is an alternative therapy that has the potential to treat active TB as an adjuvant to conventional antibiotics and a promising preventive treatment for latent TB reactivation and Mtb transmission. Moreover, Ad vector vaccines are adequate for preventing infectious diseases, including TB. Full article
(This article belongs to the Special Issue Novel Insights into Tuberculosis Research and Drug Discovery)
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16 pages, 3350 KiB  
Review
Functionalizing Dendrimers for Targeted Delivery of Bioactive Molecules to Macrophages: A Potential Treatment for Mycobacterium tuberculosis Infection—A Review
by Claudia Sanhueza, Daniela Vergara, Catalina Chávez-Aravena, Felipe Gálvez-Jiron, Emigdio Chavez-Angel and Alejandro Castro-Alvarez
Pharmaceuticals 2023, 16(10), 1428; https://doi.org/10.3390/ph16101428 - 9 Oct 2023
Cited by 5 | Viewed by 1630
Abstract
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis that replicates inside human alveolar macrophages. This disease causes significant morbidity and mortality throughout the world. According to the World Health Organization 1.4 million people died of this disease in 2021. This indicates [...] Read more.
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis that replicates inside human alveolar macrophages. This disease causes significant morbidity and mortality throughout the world. According to the World Health Organization 1.4 million people died of this disease in 2021. This indicates that despite the progress of modern medicine, improvements in diagnostics, and the development of drug susceptibility tests, TB remains a global threat to public health. In this sense, host-directed therapy may provide a new approach to the cure of TB, and the expression of miRNAs has been correlated with a change in the concentration of various inflammatory mediators whose concentrations are responsible for the pathophysiology of M. tuberculosis infection. Thus, the administration of miRNAs may help to modulate the immune response of organisms. However, direct administration of miRNAs, without adequate encapsulation, exposes nucleic acids to the activity of cytosolic nucleases, limiting their application. Dendrimers are a family of highly branched molecules with a well-defined architecture and a branched conformation which gives rise to cavities that facilitate physical immobilization, and functional groups that allow chemical interaction with molecules of interest. Additionally, dendrimers can be easily functionalized to target different cells, macrophages among them. In this sense, various studies have proposed the use of different cell receptors as target molecules to aim dendrimers at macrophages and thus release drugs or nucleic acids in the cell of interest. Based on the considerations, the primary objective of this review is to comprehensively explore the potential of functionalized dendrimers as delivery vectors for miRNAs and other therapeutic agents into macrophages. This work aims to provide insights into the use of functionalized dendrimers as an innovative approach for TB treatment, focusing on their ability to target and deliver therapeutic cargo to macrophages. Full article
(This article belongs to the Special Issue Novel Insights into Tuberculosis Research and Drug Discovery)
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38 pages, 6897 KiB  
Review
Nanocarriers in Tuberculosis Treatment: Challenges and Delivery Strategies
by Mahesh Kumar, Tarun Virmani, Girish Kumar, Rohitas Deshmukh, Ashwani Sharma, Sofia Duarte, Pedro Brandão and Pedro Fonte
Pharmaceuticals 2023, 16(10), 1360; https://doi.org/10.3390/ph16101360 - 26 Sep 2023
Cited by 8 | Viewed by 4574
Abstract
The World Health Organization identifies tuberculosis (TB), caused by Mycobacterium tuberculosis, as a leading infectious killer. Although conventional treatments for TB exist, they come with challenges such as a heavy pill regimen, prolonged treatment duration, and a strict schedule, leading to multidrug-resistant [...] Read more.
The World Health Organization identifies tuberculosis (TB), caused by Mycobacterium tuberculosis, as a leading infectious killer. Although conventional treatments for TB exist, they come with challenges such as a heavy pill regimen, prolonged treatment duration, and a strict schedule, leading to multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. The rise of MDR strains endangers future TB control. Despite these concerns, the hunt for an efficient treatment continues. One breakthrough has been the use of nanotechnology in medicines, presenting a novel approach for TB treatment. Nanocarriers, such as lipid nanoparticles, nanosuspensions, liposomes, and polymeric micelles, facilitate targeted delivery of anti-TB drugs. The benefits of nanocarriers include reduced drug doses, fewer side effects, improved drug solubility, better bioavailability, and improved patient compliance, speeding up recovery. Additionally, nanocarriers can be made even more targeted by linking them with ligands such as mannose or hyaluronic acid. This review explores these innovative TB treatments, including studies on nanocarriers containing anti-TB drugs and related patents. Full article
(This article belongs to the Special Issue Novel Insights into Tuberculosis Research and Drug Discovery)
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18 pages, 3747 KiB  
Review
Bibliometric Review on New Possibilities of Antimycobacterial Agents: Exploring Siderophore Desferrioxamine’s Applications as an Antimicrobial Agent
by Patrícia Vieira de Oliveira, Roseane Lustosa de Santana Lira, Rafael de Abreu Lima, Yasmim Costa Mendes, Antenor Bezerra Martins, Bruna de Oliveira de Melo, Millena Ferreira Goiano, Rivaldo Lira Filho, Flávia Baluz Bezerra de Farias Nunes, Amanda Silva dos Santos Aliança, Wellyson da Cunha Araújo Firmo, Rafael Cardoso Carvalho, Adrielle Zagmignan and Eduardo Martins de Sousa
Pharmaceuticals 2023, 16(9), 1335; https://doi.org/10.3390/ph16091335 - 21 Sep 2023
Cited by 2 | Viewed by 1601
Abstract
Mycobacteria cause tuberculosis and other serious diseases. Understanding their mechanisms of resistance to our immune system and exploring novel drugs are critical strategies to combat infections. A bibliometric analysis was performed to identify publication trends and critical research areas in the field of [...] Read more.
Mycobacteria cause tuberculosis and other serious diseases. Understanding their mechanisms of resistance to our immune system and exploring novel drugs are critical strategies to combat infections. A bibliometric analysis was performed to identify publication trends and critical research areas in the field of the antimicrobial activity of desferrioxamine. A total of twenty-four publications on the topic, from 2012 to 2023, were retrieved from databases including Web of Science, Scopus, PubMed, and Embase, using specific keywords. The quality of the publications was assessed using impact and productivity metrics, with an average annual publication rate of 2.1 articles. The United States emerged as the most productive country, with medicine (23.4%, 11 publications) and biochemistry, genetics, and molecular biology (21.3%, 10 publications) as the top research fields. The five most cited publications accounted for 672 citations, with a relatively low h-index (11:11). In conclusion, there has been a lack of publications on this topic in the last decade. The United States dominates production and publication in this area, and there appears to be limited exchange of knowledge, ideas, and technology within the field. Therefore, fostering international cooperation through funding is essential to facilitate further research and development of desferrioxamine-related studies. Full article
(This article belongs to the Special Issue Novel Insights into Tuberculosis Research and Drug Discovery)
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38 pages, 2389 KiB  
Review
An Insight into Advances in Developing Nanotechnology Based Therapeutics, Drug Delivery, Diagnostics and Vaccines: Multidimensional Applications in Tuberculosis Disease Management
by Hitesh Chopra, Yugal Kishore Mohanta, Pradipta Ranjan Rauta, Ramzan Ahmed, Saurov Mahanta, Piyush Kumar Mishra, Paramjot Panda, Ali A. Rabaan, Ahmad A. Alshehri, Basim Othman, Mohammed Abdulrahman Alshahrani, Ali S. Alqahtani, Baneen Ali AL Basha and Kuldeep Dhama
Pharmaceuticals 2023, 16(4), 581; https://doi.org/10.3390/ph16040581 - 12 Apr 2023
Cited by 15 | Viewed by 4966
Abstract
Tuberculosis (TB), one of the deadliest contagious diseases, is a major concern worldwide. Long-term treatment, a high pill burden, limited compliance, and strict administration schedules are all variables that contribute to the development of MDR and XDR tuberculosis patients. The rise of multidrug-resistant [...] Read more.
Tuberculosis (TB), one of the deadliest contagious diseases, is a major concern worldwide. Long-term treatment, a high pill burden, limited compliance, and strict administration schedules are all variables that contribute to the development of MDR and XDR tuberculosis patients. The rise of multidrug-resistant strains and a scarcity of anti-TB medications pose a threat to TB control in the future. As a result, a strong and effective system is required to overcome technological limitations and improve the efficacy of therapeutic medications, which is still a huge problem for pharmacological technology. Nanotechnology offers an interesting opportunity for accurate identification of mycobacterial strains and improved medication treatment possibilities for tuberculosis. Nano medicine in tuberculosis is an emerging research field that provides the possibility of efficient medication delivery using nanoparticles and a decrease in drug dosages and adverse effects to boost patient compliance with therapy and recovery. Due to their fascinating characteristics, this strategy is useful in overcoming the abnormalities associated with traditional therapy and leads to some optimization of the therapeutic impact. It also decreases the dosing frequency and eliminates the problem of low compliance. To develop modern diagnosis techniques, upgraded treatment, and possible prevention of tuberculosis, the nanoparticle-based tests have demonstrated considerable advances. The literature search was conducted using Scopus, PubMed, Google Scholar, and Elsevier databases only. This article examines the possibility of employing nanotechnology for TB diagnosis, nanotechnology-based medicine delivery systems, and prevention for the successful elimination of TB illnesses. Full article
(This article belongs to the Special Issue Novel Insights into Tuberculosis Research and Drug Discovery)
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