Tuberculosis: Challenges to Improve the Treatment

Lima, Mariana Moreira; Trindade, Ariane Biolcati; Carnavalli, Flávia; Melchior, Aylime Castanho Bolognesi; Chin, Chung Man; Santos, Jean Leandro dos

doi:10.2174/1574884708666131229124215

Cited by 7 publications

(4 citation statements)

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“…The emergence of X/MDR strains (Extensively/multi drug-resistant TB) has complicated the scenario thereby necessitating several groups to focus on newer targets, synthesis of novel compounds and explore natural products that can serve as leads for the design of anti-tubercular drugs (Palomino et al, 2009; Lima et al, 2015; Zumla, 2015). Among the targets, Filamentous temperature-sensitive mutant Z (FtsZ) protein is an essential bacterial protein which comprises of nucleotide binding N and C-terminal domains with the (tubulin)-like synergy loop (T7 loop).…”

Section: Introductionmentioning

confidence: 99%

Mutation at G103 of MtbFtsZ Altered their Sensitivity to Coumarins

et al. 2017

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Coumarins are natural polyphenol lactones comprising of fused rings of benzene and α-pyrone. The current study demonstrates the inhibitory effect of coumarins with various substitutions on Mycobacterium smegmatis mc2 155. We also demonstrate the effect of pomegranate (Punica granatum) extract containing ellagic acid, on M. smegmatis as well as their affect on MtbFtsZ (FtsZ from Mycobacterium tuberculosis). The ellagic acid extracts from pomegranate peels inhibit mycobacteria with a MIC of 25 μM and 0.3 to 3.5 mg/mL, respectively, but failed to inhibit the polymerization of MtbFtsZ. However, the coumarins were shown to inhibit the polymerization and GTPase activity of the protein as well as have an inhibitory affect on M. smegmatis mc2 155. Docking of the most active coumarin (7-Dimethyl-4-methyl coumarin with MIC of 38.7 μM) to the GTP binding site suggests that it interacted with the G103 residue. Based on the docking results two mutants of varying activity (G103S and G103A) were constructed to elucidate the interaction of MtbFtsZ and coumarins. Mutation of G103 with Serine (a bulky group) results in an inactive mutant and substitution with alanine produces a variant that retains most of the activity of the wild type. There is a disruption of the protofilament formation of the MtbFtsZ upon interaction with coumarins as demonstrated by TEM. The coumarins increase the length of Mycobacteria five times and MtbFtsZ localization is disturbed. The mutant proteins altered the GTPase and polymerization activity of coumarins as compared to wild type protein. The results here support that coumarins inhibit proliferation of Mycobacteria by targeting the assembly of MtbFtsZ and provide the possible binding site of coumarins on MtbFtsZ. This study may aid in the design of natural products as anti-mycobacterial agents. The currently reported GTP analogs for FtsZ are toxic to the human cell lines; natural coumarins targeting the GTP binding site of MtbFtsZ may hold promise as an important drug lead for tuberculosis treatment.

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Section: Introductionmentioning

confidence: 99%

Mutation at G103 of MtbFtsZ Altered their Sensitivity to Coumarins

et al. 2017

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“…TB remains a leading cause of morbidity and mortality in many countries. Current anti-TB treatments have several problems, including the development of multidrug resistance and human immunodeficiency virus (HIV) coinfection [ 1 , 2 ]. TB usually affects the lungs but can also affect other parts of the body, such as the brain, intestines, kidneys, and/or the spine [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Neuron-specific enolase as a novel biomarker reflecting tuberculosis activity and treatment response

Nam

Jeong

Jang

et al. 2016

Korean J Intern Med

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Background/Aims:It is not clear which tests are indicative of the activity and severity of tuberculosis (TB). This study aimed to investigate the predictive value of neuron-specific enolase (NSE) and to determine the origin of NSE in TB patients.Methods:A single-center retrospective analysis was conducted on newly diagnosed TB patients between January and December 2010. Patients were categorized into one of two disease groups (focal segmental or extensive) based on chest X-ray. Pre- and post-treatment NSE concentrations were evaluated. To determine the origin of serum NSE concentration, NSE staining was compared with macrophage-specific CD68 staining in lung tissues and with a tissue microarray using immunohistochemistry and immunofluorescence.Results:A total of 60 newly diagnosed TB patients were analyzed. In TB patients, NSE serum concentration was significantly increased and NSE level decreased after treatment (p < 0.001). In proportion to serum high-sensitivity C-reactive protein concentration, the mean serum concentration of NSE in the extensive group (25.12 ng/mL) was significantly higher than that in the focal segmental group (20.23 ng/mL, p = 0.04). Immunohistochemical staining revealed a large number of macrophages that stained positively for both NSE and CD68 in TB tissues. In addition, NSE signals mostly co-localized with CD68 signals in the tissue microarray of TB patients.Conclusions:Our results suggest that NSE may be a practical parameter that can be used to monitor TB activity and treatment response. Elevated serum NSE level originates, at least in part, from macrophages in granulomatous lesions.

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“…Despite extensive attempts to control and eradicate TB, it remains a prominent global public health concern. The current drug regime used for TB treatment has many side effects [ 49 ], as well as the emergence of drug-resistant strains further complicates TB control efforts [ 50 ]. This pressing concern demands the development of a novel anti-TB drug, which led us to explore the potential of a probiotic strain, Lactocaseibacillus rhamnosus PMC203, to reduce M. tuberculosis burden through stimulation of autophagy, an essential component of the body’s natural defense system.…”

Section: Discussionmentioning

confidence: 99%

Exploring the potential of Lactocaseibacillus rhamnosus PMC203 in inducing autophagy to reduce the burden of Mycobacterium tuberculosis

Rahim,

Seo,

Kim

et al. 2024

Med Microbiol Immunol

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Mycobacterium tuberculosis, a lethal pathogen in human history, causes millions of deaths annually, which demands the development of new concepts of drugs. Considering this fact, earlier research has explored the anti-tuberculosis potential of a probiotic strain, Lactocaseibacillus rhamnosus PMC203, leading to a subsequent focus on the molecular mechanism involved in its effect, particularly on autophagy. In this current study, immunoblotting-based assay exhibited a remarkable expression of autophagy marker LC3-II in the PMC203 treated group compared to an untreated group. A remarkable degradation of p62 was also noticed within treated cells compared to control. Furthermore, the immunofluorescence-based assay showed significant fold change in fluorescence intensity for alexa-647-LC3 and alexa-488-LC3, whereas p62 was degraded noticeably. Moreover, lysosomal biogenesis generation was elevated significantly in terms of LAMP1 and acidic vesicular organelles. As a result, PMC203-induced autophagy played a vital role in reducing M. tuberculosis burden within the macrophages in treated groups compared to untreated group. A colony -forming unit assay also revealed a significant reduction in M. tuberculosis in the treated cells over time. Additionally, the candidate strain significantly upregulated the expression of autophagy induction and lysosomal biogenesis genes. Together, these results could enrich our current knowledge of probiotics-mediated autophagy in tuberculosis and suggest its implications for innovatively managing tuberculosis.

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Tuberculosis: Challenges to Improve the Treatment

Cited by 7 publications

References 0 publications

Mutation at G103 of MtbFtsZ Altered their Sensitivity to Coumarins

Mutation at G103 of MtbFtsZ Altered their Sensitivity to Coumarins

Neuron-specific enolase as a novel biomarker reflecting tuberculosis activity and treatment response

Exploring the potential of Lactocaseibacillus rhamnosus PMC203 in inducing autophagy to reduce the burden of Mycobacterium tuberculosis

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