Marine Natural Products and Drug Resistance in Latent Tuberculosis

Khan, Muhammad Tahir; Kaushik, Aman Chandra; Bhatti, Aamer Iqbal; Zhang, Yujuan; Zhang, Shulin; Wei, Amie Jinghua; Malik, Shaukat Iqbal; Wei, Dong

doi:10.3390/md17100549

Cited by 14 publications

(5 citation statements)

References 80 publications

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“…Five compounds extracted from the marine sponge Haliclona sp. were found with properties against latent MTB isolates [25]. In our previous study, we obtained 12 compounds from the cultures of the deep-sea-derived fungus Aspergillus sp.…”

Section: Discussionmentioning

confidence: 99%

Marine-Fungi-Derived Gliotoxin Promotes Autophagy to Suppress Mycobacteria tuberculosis Infection in Macrophage

Fu,

Luo,

Lin

et al. 2023

Marine Drugs

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The Mycobacterium tuberculosis (MTB) infection causes tuberculosis (TB) and has been a long-standing public-health threat. It is urgent that we discover novel antitubercular agents to manage the increased incidence of multidrug-resistant (MDR) or extensively drug-resistant (XDR) strains of MTB and tackle the adverse effects of the first- and second-line antitubercular drugs. We previously found that gliotoxin (1), 12, 13-dihydroxy-fumitremorgin C (2), and helvolic acid (3) from the cultures of a deep-sea-derived fungus, Aspergillus sp. SCSIO Ind09F01, showed direct anti-TB effects. As macrophages represent the first line of the host defense system against a mycobacteria infection, here we showed that the gliotoxin exerted potent anti-tuberculosis effects in human THP-1-derived macrophages and mouse-macrophage-leukemia cell line RAW 264.7, using CFU assay and laser confocal scanning microscope analysis. Mechanistically, gliotoxin apparently increased the ratio of LC3-II/LC3-I and Atg5 expression, but did not influence macrophage polarization, IL-1β, TNF-a, IL-10 production upon MTB infection, or ROS generation. Further study revealed that 3-MA could suppress gliotoxin-promoted autophagy and restore gliotoxin-inhibited MTB infection, indicating that gliotoxin-inhibited MTB infection can be treated through autophagy in macrophages. Therefore, we propose that marine fungi-derived gliotoxin holds the promise for the development of novel drugs for TB therapy.

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Section: Discussionmentioning

confidence: 99%

Marine-Fungi-Derived Gliotoxin Promotes Autophagy to Suppress Mycobacteria tuberculosis Infection in Macrophage

Fu,

Luo,

Lin

et al. 2023

Marine Drugs

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“…Bacterial RNA polymerase inhibitor [84] Various natural and synthetic flavonoids were reported for the effective treatment of TB [85]. Also, some compounds extracted from Haliclona, a marine sponge, exhibited strong activity versus mycobacteria [86]. The potent efficacy of macrolides, such as SEQ-503, SEQ-9, clarithromycin, and sequanamycin A, was demonstrated in both in vitro and in vivo models of TB.…”

Section: Glycosylated Macrolide Tiacumicin From the Soil Bacterium Da...mentioning

confidence: 99%

New Alternatives in the Fight against Tuberculosis: Possible Targets for Resistant Mycobacteria

Rodríguez-Bustamante,

Gómez-Manzo,

De Obeso Fernández del Valle

et al. 2023

Processes

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Tuberculosis (TB) is a bacterial disease that remains a global health threat due to the millions of deaths attributed to it each year. The emergence of drug resistance has exacerbated and further increased the challenges in the fight against this illness. Despite the preventive measures using the application of the Bacillus Calmette-Guérin vaccine, the desired immunization outcome is not as high as expected. Conventional TB treatments exhibit serious limitations, such as adverse effects and prolonged duration, leading to a pressing need for alternative and more effective treatment options. Despite significant efforts, it took nearly four decades for diarylquinoline to become the most recently approved medicine for this disease. In addition, various possibilities, such as the usage of medications used for many other conditions (repurposed drugs), have been explored in order to speed up the process of achieving faster outcomes. Natural compounds derived from various sources (microorganisms, plants, and animals) have emerged as potential candidates for combating TB due to their chemical diversity and their unique modes of action. Finally, efforts towards the generation of novel vaccines have received considerable attention. The goal of this paper was to perform an analysis of the current state of treating drug-resistant TB and to evaluate possible approaches to this complicated challenge. Our focus is centered on highlighting new alternatives that can be used to combat resistant strains, which have potentiated the health crisis that TB represents.

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“…PZA is a prodrug, activated by MTB encoded pncA into POA, targeting RpsA. POA-resistance may occur when mutations arise at the C-terminus of RpsA (MtRpsA CTD ), causing conformational changes (Yang et al, 2015;Huang et al, 2019;Khan et al, 2019a;Shi et al, 2019;Singh et al, 2019;Zhi et al, 2019). Residues in the fourth S1 domain, which is known as a highly conserved region, were able to interact with POA (Shi et al, 2011;Yang et al, 2015).…”

Section: Mutants Selection In Rpsamentioning

confidence: 99%

Gibbs Free Energy Calculation of Mutation in PncA and RpsA Associated With Pyrazinamide Resistance

Khan

Ali

Zeb³

et al. 2020

Front. Mol. Biosci.

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A central approach for better understanding the forces involved in maintaining protein structures is to investigate the protein folding and thermodynamic properties. The effect of the folding process is often disturbed in mutated states. To explore the dynamic properties behind mutations, molecular dynamic (MD) simulations have been widely performed, especially in unveiling the mechanism of drug failure behind mutation. When comparing wild type (WT) and mutants (MTs), the structural changes along with solvation free energy (SFE), and Gibbs free energy (GFE) are calculated after the MD simulation, to measure the effect of mutations on protein structure. Pyrazinamide (PZA) is one of the first-line drugs, effective against latent Mycobacterium tuberculosis isolates, affecting the global TB control program 2030. Resistance to this drug emerges due to mutations in pncA and rpsA genes, encoding pyrazinamidase (PZase) and ribosomal protein S1 (RpsA) respectively. The question of how the GFE may be a measure of PZase and RpsA stabilities, has been addressed in the current review. The GFE and SFE of MTs have been compared with WT, which were already found to be PZA-resistant. WT structures attained a more stable state in comparison with MTs. The physiological effect of a mutation in PZase and RpsA may be due to the difference in energies. This difference between WT and MTs, depicted through GFE plots, might be useful in predicting the stability and PZA-resistance behind mutation. This study provides useful information for better management of drug resistance, to control the global TB problem.

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Marine Natural Products and Drug Resistance in Latent Tuberculosis

Cited by 14 publications

References 80 publications

Marine-Fungi-Derived Gliotoxin Promotes Autophagy to Suppress Mycobacteria tuberculosis Infection in Macrophage

Marine-Fungi-Derived Gliotoxin Promotes Autophagy to Suppress Mycobacteria tuberculosis Infection in Macrophage

New Alternatives in the Fight against Tuberculosis: Possible Targets for Resistant Mycobacteria

Gibbs Free Energy Calculation of Mutation in PncA and RpsA Associated With Pyrazinamide Resistance

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