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Biomolecules
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Virulence Factors in Mycobacterium tuberculosis Infection: Structural and Functional Studies
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Virulence Factors in Mycobacterium tuberculosis Infection: Structural and Functional Studies

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Biological Factors".

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 14008

Special Issue Editors

Dr. Rita Berisio

E-Mail Website
Guest Editor
Institute of Biostructures and Bioimaging, CNR, Via Mezzocannone 16, I-80134 Napoli, Italy
Interests: structural biology; biophysics; infectious diseases; vaccine
Special Issues, Collections and Topics in MDPI journals
Dr. Alessia Ruggiero

E-Mail Website
Guest Editor
Institute of Biostructures and Bioimaging, CNR, Via Mezzocannone 16, I-80134 Napoli, Italy
Interests: structural biology; molecular biology; biochemistry; infection disease
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In this Special issue of Biomolecules titled “Virulence Factors in Mycobacterium tuberculosis Infection: Structural and Functional Studies”, we aim to provide a thorough account of the latest progress in the structural and functional characterization of the most important players in TB infection.

Among respiratory pathogens, tuberculosis (TB) is one of the leading causes of death by infection, especially in immunocompromised patients (e.g., those with HIV). Rising rates of TB antibiotic resistance have been recorded around the world, making these bacteria immune to anti-TB drugs. New antibacterial strategies are needed to manage the global challenge of antimicrobial resistance in TB infection. To address this issue, comprehensive knowledge of important macromolecules regulating M. tuberculosis physiopathology is essential.

In the last few decades, extensive studies have been performed aimed at the structural and functional characterization of the key molecular players involved in TB life cycle and virulence. A significant contribution has come from the determination of several structures involved in regulatory mechanisms, such as cell division, peptidoglycan synthesis and degradation, and host–pathogen interaction.

This Special Issue offers an open access platform that aims to bring together a collection of research articles, reviews, and perspectives to address various aspects of M. tuberculosis life cycle for the development of therapeutic tools against TB.

Dr. Rita Berisio
Dr. Alessia Ruggiero
Guest Editors

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. Biomolecules 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 2700 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

  • structural biology
  • tuberculosis
  • function
  • molecular mechanism

Related Special Issue

Published Papers (7 papers)

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Editorial

Jump to: Research, Review

3 pages, 186 KiB  
Editorial
Virulence Factors in Mycobacterium tuberculosis Infection: Structural and Functional Studies
by Rita Berisio and Alessia Ruggiero
Biomolecules 2023, 13(8), 1201; https://doi.org/10.3390/biom13081201 - 31 Jul 2023
Viewed by 787
Abstract
Tuberculosis (TB) remains one of the main causes of death by infection, especially in immunocompromised patients [...] Full article
(This article belongs to the Special Issue Virulence Factors in Mycobacterium tuberculosis Infection: Structural and Functional Studies)

Research

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21 pages, 5105 KiB  
Article
Evaluation of Acute and Sub-Acute Toxicity, Oxidative Stress and Molecular Docking of Two Nitrofuranyl Amides as Promising Anti-Tuberculosis Agents
by Simeon Dimitrov, Ivaylo Slavchev, Rumyana Simeonova, Milka Mileva, Tania Pencheva, Stanislav Philipov, Almira Georgieva, Elina Tsvetanova, Yoanna Teneva, Nadezhda Rimpova, Georgi Dobrikov and Violeta Valcheva
Biomolecules 2023, 13(8), 1174; https://doi.org/10.3390/biom13081174 - 28 Jul 2023
Cited by 1 | Viewed by 1184
Abstract
Tuberculosis (TB) remains a widespread infectious disease and one of the top 10 causes of death worldwide. Nevertheless, despite significant advances in the development of new drugs against tuberculosis, many therapies and preventive measures do not lead to the expected favorable health results [...] Read more.
Tuberculosis (TB) remains a widespread infectious disease and one of the top 10 causes of death worldwide. Nevertheless, despite significant advances in the development of new drugs against tuberculosis, many therapies and preventive measures do not lead to the expected favorable health results for various reasons. The aim of this study was to evaluate the acute and sub-acute toxicity and oxidative stress of two selected nitrofuranyl amides with high in vitro antimycobacterial activity. In addition, molecular docking studies were performed on both compounds to elucidate the possibilities for further development of new anti-tuberculosis candidates with improved efficacy, selectivity, and pharmacological parameters. Acute toxicity tests showed that no changes were observed in the skin, coat, eyes, mucous membranes, secretions, and vegetative activity in mice. The histological findings include features consistent with normal histological architecture without being associated with concomitant pathological conditions. The observed oxidative stress markers indicated that the studied compounds disturbed the oxidative balance in the mouse liver. Based on the molecular docking, compound DO-190 showed preferable binding energies compared to DO-209 in three out of four targets, while both compounds showed promising protein–ligand interactions. Thus, both studied compounds displayed promising activity with low toxicity and can be considered for further evaluation and/or lead optimization. Full article
(This article belongs to the Special Issue Virulence Factors in Mycobacterium tuberculosis Infection: Structural and Functional Studies)
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15 pages, 2900 KiB  
Article
Regulation of CRISPR-Associated Genes by Rv1776c (CasR) in Mycobacterium tuberculosis
by Wenping Wei, Xiaofang Jiang, Li Zhang, Yunjun Yan, Jinyong Yan, Li Xu, Chun-Hui Gao and Min Yang
Biomolecules 2023, 13(2), 400; https://doi.org/10.3390/biom13020400 - 20 Feb 2023
Cited by 2 | Viewed by 1714
Abstract
The CRISPR-Cas system is an adaptive immune system for many bacteria and archaea to defend against foreign nucleic acid invasion, and this system is conserved in the genome of M. tuberculosis (Mtb). Although the CRISPR-Cas system-mediated immune defense mechanism has been [...] Read more.
The CRISPR-Cas system is an adaptive immune system for many bacteria and archaea to defend against foreign nucleic acid invasion, and this system is conserved in the genome of M. tuberculosis (Mtb). Although the CRISPR-Cas system-mediated immune defense mechanism has been revealed in Mtb, the regulation of cas gene expression is poorly understood. In this study, we identified a transcription factor, CasR (CRISPR-associated protein repressor, encoded by Rv1776c), and it could bind to the upstream DNA sequence of the CRISPR-Cas gene cluster and regulate the expression of cas genes. EMSA and ChIP assays confirmed that CasR could interact with the upstream sequence of the csm6 promoter, both in vivo and in vitro. Furthermore, DNA footprinting assay revealed that CasR recognized a 20 bp palindromic sequence motif and negatively regulated the expression of csm6. In conclusion, our research elucidates the regulatory effect of CasR on the expression of CRISPR-associated genes in mycobacteria, thus providing insight into gene expression regulation of the CRISPR-Cas system. Full article
(This article belongs to the Special Issue Virulence Factors in Mycobacterium tuberculosis Infection: Structural and Functional Studies)
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16 pages, 2641 KiB  
Article
A Dendritic Cell-Activating Rv1876 Protein Elicits Mycobacterium Bovis BCG-Prime Effect via Th1-Immune Response
by Seunga Choi, Han-Gyu Choi, Yong Woo Back, Hye-Soo Park, Kang-In Lee, Sintayehu Kebede Gurmessa, Thuy An Pham and Hwa-Jung Kim
Biomolecules 2021, 11(9), 1306; https://doi.org/10.3390/biom11091306 - 03 Sep 2021
Cited by 9 | Viewed by 2141
Abstract
The widely administered tuberculosis (TB) vaccine, Bacillus Calmette-Guerin (BCG), is the only licensed vaccine, but has highly variable efficiency against childhood and pulmonary TB. Therefore, the BCG prime-boost strategy is a rational solution for the development of new TB vaccines. Studies have shown [...] Read more.
The widely administered tuberculosis (TB) vaccine, Bacillus Calmette-Guerin (BCG), is the only licensed vaccine, but has highly variable efficiency against childhood and pulmonary TB. Therefore, the BCG prime-boost strategy is a rational solution for the development of new TB vaccines. Studies have shown that Mycobacterium tuberculosis (Mtb) culture filtrates contain proteins that have promising vaccine potential. In this study, Rv1876 bacterioferritin was identified from the culture filtrate fraction with strong immunoreactivity. Its immunobiological potential has not been reported previously. We found that recombinant Rv1876 protein induced dendritic cells’ (DCs) maturation by MAPK and NF-κB signaling activation, induced a T helper type 1 cell-immune response, and expanded the population of the effector/memory T cell. Boosting BCG with Rv1876 protein enhanced the BCG-primed Th1 immune response and reduced the bacterial load in the lung compared to those of BCG alone. Thus, Rv1876 is a good target for the prime-boost strategy. Full article
(This article belongs to the Special Issue Virulence Factors in Mycobacterium tuberculosis Infection: Structural and Functional Studies)
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14 pages, 14335 KiB  
Article
Structural Changes in the Cap of Rv0183/mtbMGL Modulate the Shape of the Binding Pocket
by Christoph Grininger, Mario Leypold, Philipp Aschauer, Tea Pavkov-Keller, Lina Riegler-Berket, Rolf Breinbauer and Monika Oberer
Biomolecules 2021, 11(9), 1299; https://doi.org/10.3390/biom11091299 - 01 Sep 2021
Cited by 2 | Viewed by 2026
Abstract
Tuberculosis continues to be a major threat to the human population. Global efforts to eradicate the disease are ongoing but are hampered by the increasing occurrence of multidrug-resistant strains of Mycobacterium tuberculosis. Therefore, the development of new treatment, and the exploration of [...] Read more.
Tuberculosis continues to be a major threat to the human population. Global efforts to eradicate the disease are ongoing but are hampered by the increasing occurrence of multidrug-resistant strains of Mycobacterium tuberculosis. Therefore, the development of new treatment, and the exploration of new druggable targets and treatment strategies, are of high importance. Rv0183/mtbMGL, is a monoacylglycerol lipase of M. tuberculosis and it is involved in providing fatty acids and glycerol as building blocks and as an energy source. Since the lipase is expressed during the dormant and active phase of an infection, Rv0183/mtbMGL is an interesting target for inhibition. In this work, we determined the crystal structures of a surface-entropy reduced variant K74A Rv0183/mtbMGL in its free form and in complex with a substrate mimicking inhibitor. The two structures reveal conformational changes in the cap region that forms a major part of the substrate/inhibitor binding region. We present a completely closed conformation in the free form and semi-closed conformation in the ligand-bound form. These conformations differ from the previously published, completely open conformation of Rv0183/mtbMGL. Thus, this work demonstrates the high conformational plasticity of the cap from open to closed conformations and provides useful insights into changes in the substrate-binding pocket, the target of potential small-molecule inhibitors. Full article
(This article belongs to the Special Issue Virulence Factors in Mycobacterium tuberculosis Infection: Structural and Functional Studies)
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Review

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18 pages, 5385 KiB  
Review
Emerging Extracellular Molecular Targets for Innovative Pharmacological Approaches to Resistant Mtb Infection
by Alice Italia, Mohammed Monsoor Shaik and Francesco Peri
Biomolecules 2023, 13(6), 999; https://doi.org/10.3390/biom13060999 - 16 Jun 2023
Cited by 2 | Viewed by 1625
Abstract
Emerging pharmacological strategies that target major virulence factors of antibiotic-resistant Mycobacterium tuberculosis (Mtb) are presented and discussed. This review is divided into three parts corresponding to structures and functions important for Mtb pathogenicity: the cell wall, the lipoarabinomannan, and the secretory proteins. Within [...] Read more.
Emerging pharmacological strategies that target major virulence factors of antibiotic-resistant Mycobacterium tuberculosis (Mtb) are presented and discussed. This review is divided into three parts corresponding to structures and functions important for Mtb pathogenicity: the cell wall, the lipoarabinomannan, and the secretory proteins. Within the cell wall, we further focus on three biopolymeric sub-components: mycolic acids, arabinogalactan, and peptidoglycan. We present a comprehensive overview of drugs and drug candidates that target cell walls, envelopes, and secretory systems. An understanding at a molecular level of Mtb pathogenesis is provided, and potential future directions in therapeutic strategies are suggested to access new drugs to combat the growing global threat of antibiotic-resistant Mtb infection. Full article
(This article belongs to the Special Issue Virulence Factors in Mycobacterium tuberculosis Infection: Structural and Functional Studies)
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16 pages, 1386 KiB  
Review
ESAT-6 a Major Virulence Factor of Mycobacterium tuberculosis
by Elsa Anes, David Pires, Manoj Mandal and José Miguel Azevedo-Pereira
Biomolecules 2023, 13(6), 968; https://doi.org/10.3390/biom13060968 - 09 Jun 2023
Cited by 5 | Viewed by 3427
Abstract
Mycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis (TB), is one of the most successfully adapted human pathogens. Human-to-human transmission occurs at high rates through aerosols containing bacteria, but the pathogen evolved prior to the establishment of crowded populations. Mtb has developed [...] Read more.
Mycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis (TB), is one of the most successfully adapted human pathogens. Human-to-human transmission occurs at high rates through aerosols containing bacteria, but the pathogen evolved prior to the establishment of crowded populations. Mtb has developed a particular strategy to ensure persistence in the host until an opportunity for transmission arises. It has refined its lifestyle to obviate the need for virulence factors such as capsules, flagella, pili, or toxins to circumvent mucosal barriers. Instead, the pathogen uses host macrophages, where it establishes intracellular niches for its migration into the lung parenchyma and other tissues and for the induction of long-lived latency in granulomas. Finally, at the end of the infection cycle, Mtb induces necrotic cell death in macrophages to escape to the extracellular milieu and instructs a strong inflammatory response that is required for the progression from latency to disease and transmission. Common to all these events is ESAT-6, one of the major virulence factors secreted by the pathogen. This narrative review highlights the recent advances in understanding the role of ESAT-6 in hijacking macrophage function to establish successful infection and transmission and its use as a target for the development of diagnostic tools and vaccines. Full article
(This article belongs to the Special Issue Virulence Factors in Mycobacterium tuberculosis Infection: Structural and Functional Studies)
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