Editorial

3 pages, 185 KiB

Open AccessEditorial

New Drugs and Novel Cellular Targets against Tuberculosis

by Giulia Degiacomi, Vadim Makarov, Maria Rosalia Pasca and Laurent Roberto Chiarelli

Int. J. Mol. Sci. 2022, 23(22), 13680; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232213680 - 08 Nov 2022

Cited by 1 | Viewed by 1078

Mycobacterium tuberculosis (Mtb) is the etiological agent of tuberculosis (TB), one of the most life-threatening communicable diseases, which causes 10 million new cases each year and results in an estimated 1 [...] Full article

(This article belongs to the Special Issue New Drugs and Novel Cellular Targets against Tuberculosis)

Research

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25 pages, 5951 KiB

Open AccessArticle

Effect of Curcumin in Experimental Pulmonary Tuberculosis: Antimycobacterial Activity in the Lungs and Anti-Inflammatory Effect in the Brain

by Jacqueline V. Lara-Espinosa, María Fernanda Arce-Aceves, Manuel O. López-Torres, Vasti Lozano-Ordaz, Dulce Mata-Espinosa, Jorge Barrios-Payán, Carlos Alfredo Silva-Islas, Perla D. Maldonado, Brenda Marquina-Castillo and Rogelio Hernández-Pando

Int. J. Mol. Sci. 2022, 23(4), 1964; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23041964 - 10 Feb 2022

Cited by 8 | Viewed by 2858

Abstract

Tuberculosis (TB) is one of the ten leading causes of death worldwide. Patients with TB have been observed to suffer from depression and anxiety linked to social variables. Previous experiments found that the substantial pulmonary inflammation associated with TB causes neuroinflammation, neuronal death, [...] Read more.

Tuberculosis (TB) is one of the ten leading causes of death worldwide. Patients with TB have been observed to suffer from depression and anxiety linked to social variables. Previous experiments found that the substantial pulmonary inflammation associated with TB causes neuroinflammation, neuronal death, and behavioral impairments in the absence of brain infection. Curcumin (CUR) is a natural product with antioxidant, anti-inflammatory and antibacterial activities. In this work, we evaluated the CUR effect on the growth control of mycobacteria in the lungs and the anti-inflammatory effect in the brain using a model of progressive pulmonary TB in BALB/c mice infected with drug-sensitive mycobacteria (strain H37Rv). The results have shown that CUR decreased lung bacilli load and pneumonia of infected animals. Finally, CUR significantly decreased neuroinflammation (expression of TNF

α

, IFN

γ

and IL12) and slightly increased the levels of nuclear factor erythroid 2-related to factor 2 (Nrf2) and the brain-derived neurotrophic factor (BDNF) levels, improving behavioral status. These results suggest that CUR has a bactericidal effect and can control pulmonary mycobacterial infection and reduce neuroinflammation. It seems that CUR has a promising potential as adjuvant therapy in TB treatment. Full article

(This article belongs to the Special Issue New Drugs and Novel Cellular Targets against Tuberculosis)

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14 pages, 1978 KiB

Open AccessArticle

The Veterinary Anti-Parasitic Selamectin Is a Novel Inhibitor of the Mycobacterium tuberculosis DprE1 Enzyme

by José Manuel Ezquerra-Aznárez, Giulia Degiacomi, Henrich Gašparovič, Giovanni Stelitano, Josè Camilla Sammartino, Jana Korduláková, Paolo Governa, Fabrizio Manetti, Maria Rosalia Pasca, Laurent Roberto Chiarelli and Santiago Ramón-García

Int. J. Mol. Sci. 2022, 23(2), 771; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23020771 - 11 Jan 2022

Cited by 10 | Viewed by 2387

Abstract

Avermectins are macrocyclic lactones with anthelmintic activity. Recently, they were found to be effective against Mycobacterium tuberculosis, which accounts for one third of the worldwide deaths from antimicrobial resistance. However, their anti-mycobacterial mode of action remains to be elucidated. The activity of [...] Read more.

Avermectins are macrocyclic lactones with anthelmintic activity. Recently, they were found to be effective against Mycobacterium tuberculosis, which accounts for one third of the worldwide deaths from antimicrobial resistance. However, their anti-mycobacterial mode of action remains to be elucidated. The activity of selamectin was determined against a panel of M. tuberculosis mutants. Two strains carrying mutations in DprE1, the decaprenylphosphoryl-β-D-ribose oxidase involved in the synthesis of mycobacterial arabinogalactan, were more susceptible to selamectin. Biochemical assays against the Mycobacterium smegmatis DprE1 protein confirmed this finding, and docking studies predicted a binding site in a loop that included Leu275. Sequence alignment revealed variants in this position among mycobacterial species, with the size and hydrophobicity of the residue correlating with their MIC values; M. smegmatis DprE1 variants carrying these point mutations validated the docking predictions. However, the correlation was not confirmed when M. smegmatis mutant strains were constructed and MIC phenotypic assays performed. Likewise, metabolic labeling of selamectin-treated M. smegmatis and M. tuberculosis cells with ¹⁴C-labeled acetate did not reveal the expected lipid profile associated with DprE1 inhibition. Together, our results confirm the in vitro interactions of selamectin and DprE1 but suggest that selamectin could be a multi-target anti-mycobacterial compound. Full article

(This article belongs to the Special Issue New Drugs and Novel Cellular Targets against Tuberculosis)

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22 pages, 29020 KiB

Open AccessArticle

The Effect of Tuberculosis Antimicrobials on the Immunometabolic Profiles of Primary Human Macrophages Stimulated with Mycobacterium tuberculosis

by Christina Cahill, Dónal J. Cox, Fiona O’Connell, Sharee A. Basdeo, Karl M. Gogan, Cilian Ó’Maoldomhnaigh, Jacintha O’Sullivan, Joseph Keane and James J. Phelan

Int. J. Mol. Sci. 2021, 22(22), 12189; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212189 - 10 Nov 2021

Cited by 3 | Viewed by 2108

Abstract

Tuberculosis (TB) remains a global health challenge. Patients with drug-sensitive and drug-resistant TB undergo long, arduous, and complex treatment regimens, often involving multiple antimicrobials. While these drugs were initially implemented based on their bactericidal effects, some studies show that TB antimicrobials can also [...] Read more.

Tuberculosis (TB) remains a global health challenge. Patients with drug-sensitive and drug-resistant TB undergo long, arduous, and complex treatment regimens, often involving multiple antimicrobials. While these drugs were initially implemented based on their bactericidal effects, some studies show that TB antimicrobials can also directly affect cells of the immune system, altering their immune function. As use of these antimicrobials has been the mainstay of TB therapy for over fifty years now, it is more important than ever to understand how these antimicrobials affect key pathways of the immune system. One such central pathway, which underpins the immune response to a variety of infections, is immunometabolism, namely glycolysis and oxidative phosphorylation (OXPHOS). We hypothesise that in addition to their direct bactericidal effect on Mycobacterium tuberculosis (Mtb), current TB antimicrobials can modulate immunometabolic profiles and alter mitochondrial function in primary human macrophages. Human monocyte-derived macrophages (hMDMs) were differentiated from PBMCs isolated from healthy blood donors, and treated with four first-line and six second-line TB antimicrobials three hours post stimulation with either iH37Rv-Mtb or lipopolysaccharide (LPS). 24 h post stimulation, baseline metabolism and mitochondrial function were determined using the Seahorse Extracellular Flux Analyser. The effect of these antimicrobials on cytokine and chemokine production was also assayed using Meso Scale Discovery Multi-Array technology. We show that some of the TB antimicrobials tested can significantly alter OXPHOS and glycolysis in uninfected, iH37Rv-Mtb, and LPS-stimulated hMDMs. We also demonstrate how these antimicrobial-induced immunometabolic effects are linked with alterations in mitochondrial function. Our results show that TB antimicrobials, specifically clofazimine, can modify host immunometabolism and mitochondrial function. Moreover, clofazimine significantly increased the production of IL-6 in human macrophages that were stimulated with iH37Rv-Mtb. This provides further insight into the use of some of these TB antimicrobials as potential host-directed therapies in patients with early and active disease, which could help to inform TB treatment strategies in the future. Full article

(This article belongs to the Special Issue New Drugs and Novel Cellular Targets against Tuberculosis)

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14 pages, 2171 KiB

Open AccessArticle

Optimized Synthesis of New Thiosemicarbazide Derivatives with Tuberculostatic Activity

by Corina Popovici, Cristina-Maria Pavel, Valeriu Sunel, Corina Cheptea, Dan Gheorghe Dimitriu, Dana Ortansa Dorohoi, Diana David, Valentina Closca and Marcel Popa

Int. J. Mol. Sci. 2021, 22(22), 12139; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212139 - 09 Nov 2021

Cited by 7 | Viewed by 2059

Abstract

Original results are presented in the field of research that addresses the extension of the reaction of residue of acyl-thiosemicarbazide fixation on the structure of 5-nitrobenzimidazole by a sulphonic group. The aim of the study is the increase of new thiosemicarbazide derivatives’ applicative [...] Read more.

Original results are presented in the field of research that addresses the extension of the reaction of residue of acyl-thiosemicarbazide fixation on the structure of 5-nitrobenzimidazole by a sulphonic group. The aim of the study is the increase of new thiosemicarbazide derivatives’ applicative potential in the field of biochemistry, with a wide range of medical applications. The newly obtained compounds were characterized by using elemental analysis and spectral analysis (FT-IR and ¹H NMR). A study regarding the optimization of the chemical reactions was made. The performed in vitro biological tests confirmed the tuberculostatic activity of three newly obtained compounds against Mycobacterium tuberculosis. Full article

(This article belongs to the Special Issue New Drugs and Novel Cellular Targets against Tuberculosis)

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20 pages, 6117 KiB

Open AccessArticle

Gran1: A Granulysin-Derived Peptide with Potent Activity against Intracellular Mycobacterium tuberculosis

by Reiner Noschka, Fanny Wondany, Gönül Kizilsavas, Tanja Weil, Gilbert Weidinger, Paul Walther, Jens Michaelis and Steffen Stenger

Int. J. Mol. Sci. 2021, 22(16), 8392; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168392 - 04 Aug 2021

Cited by 12 | Viewed by 2645

Abstract

Granulysin is an antimicrobial peptide (AMP) expressed by human T-lymphocytes and natural killer cells. Despite a remarkably broad antimicrobial spectrum, its implementation into clinical practice has been hampered by its large size and off-target effects. To circumvent these limitations, we synthesized a 29 [...] Read more.

Granulysin is an antimicrobial peptide (AMP) expressed by human T-lymphocytes and natural killer cells. Despite a remarkably broad antimicrobial spectrum, its implementation into clinical practice has been hampered by its large size and off-target effects. To circumvent these limitations, we synthesized a 29 amino acid fragment within the putative cytolytic site of Granulysin (termed “Gran1”). We evaluated the antimicrobial activity of Gran1 against the major human pathogen Mycobacterium tuberculosis (Mtb) and a panel of clinically relevant non-tuberculous mycobacteria which are notoriously difficult to treat. Gran1 efficiently inhibited the mycobacterial proliferation in the low micro molar range. Super-resolution fluorescence microscopy and scanning electron microscopy indicated that Gran1 interacts with the surface of Mtb, causing lethal distortions of the cell wall. Importantly, Gran1 showed no off-target effects (cytokine release, chemotaxis, cell death) in primary human cells or zebrafish embryos (cytotoxicity, developmental toxicity, neurotoxicity, cardiotoxicity). Gran1 was selectively internalized by macrophages, the major host cell of Mtb, and restricted the proliferation of the pathogen. Our results demonstrate that the hypothesis-driven design of AMPs is a powerful approach for the identification of small bioactive compounds with specific antimicrobial activity. Gran1 is a promising component for the design of AMP-containing nanoparticles with selective activity and favorable pharmacokinetics to be pushed forward into experimental in vivo models of infectious diseases, most notably tuberculosis. Full article

(This article belongs to the Special Issue New Drugs and Novel Cellular Targets against Tuberculosis)

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Review

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15 pages, 1663 KiB

Open AccessReview

Targeting Non-Replicating Mycobacterium tuberculosis and Latent Infection: Alternatives and Perspectives (Mini-Review)

by Anna Egorova, Elena G. Salina and Vadim Makarov

Int. J. Mol. Sci. 2021, 22(24), 13317; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222413317 - 10 Dec 2021

Cited by 10 | Viewed by 3281

Abstract

Latent tuberculosis infection (LTBI) represents a major challenge to curing TB disease. Current guidelines for LTBI management include only three older drugs and their combinations—isoniazid and rifamycins (rifampicin and rifapentine). These available control strategies have little impact on latent TB elimination, and new [...] Read more.

Latent tuberculosis infection (LTBI) represents a major challenge to curing TB disease. Current guidelines for LTBI management include only three older drugs and their combinations—isoniazid and rifamycins (rifampicin and rifapentine). These available control strategies have little impact on latent TB elimination, and new specific therapeutics are urgently needed. In the present mini-review, we highlight some of the alternatives that may potentially be included in LTBI treatment recommendations and a list of early-stage prospective small molecules that act on drug targets specific for Mycobacterium tuberculosis latency. Full article

(This article belongs to the Special Issue New Drugs and Novel Cellular Targets against Tuberculosis)

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39 pages, 24438 KiB

Open AccessReview

Drug Discovery for Mycobacterium tuberculosis Using Structure-Based Computer-Aided Drug Design Approach

by Murtala A. Ejalonibu, Segun A. Ogundare, Ahmed A. Elrashedy, Morufat A. Ejalonibu, Monsurat M. Lawal, Ndumiso N. Mhlongo and Hezekiel M. Kumalo

Int. J. Mol. Sci. 2021, 22(24), 13259; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222413259 - 09 Dec 2021

Cited by 30 | Viewed by 8353

Abstract

Developing new, more effective antibiotics against resistant Mycobacterium tuberculosis that inhibit its essential proteins is an appealing strategy for combating the global tuberculosis (TB) epidemic. Finding a compound that can target a particular cavity in a protein and interrupt its enzymatic activity is [...] Read more.

Developing new, more effective antibiotics against resistant Mycobacterium tuberculosis that inhibit its essential proteins is an appealing strategy for combating the global tuberculosis (TB) epidemic. Finding a compound that can target a particular cavity in a protein and interrupt its enzymatic activity is the crucial objective of drug design and discovery. Such a compound is then subjected to different tests, including clinical trials, to study its effectiveness against the pathogen in the host. In recent times, new techniques, which involve computational and analytical methods, enhanced the chances of drug development, as opposed to traditional drug design methods, which are laborious and time-consuming. The computational techniques in drug design have been improved with a new generation of software used to develop and optimize active compounds that can be used in future chemotherapeutic development to combat global tuberculosis resistance. This review provides an overview of the evolution of tuberculosis resistance, existing drug management, and the design of new anti-tuberculosis drugs developed based on the contributions of computational techniques. Also, we show an appraisal of available software and databases on computational drug design with an insight into the application of this software and databases in the development of anti-tubercular drugs. The review features a perspective involving machine learning, artificial intelligence, quantum computing, and CRISPR combination with available computational techniques as a prospective pathway to design new anti-tubercular drugs to combat resistant tuberculosis. Full article

(This article belongs to the Special Issue New Drugs and Novel Cellular Targets against Tuberculosis)

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