scholarly journals Biofilm formation in the lung contributes to virulence and drug tolerance of Mycobacterium tuberculosis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Poushali Chakraborty ◽  
Sapna Bajeli ◽  
Deepak Kaushal ◽  
Bishan Dass Radotra ◽  
Ashwani Kumar
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Immune System ◽  
Biofilm Formation ◽  
Antimycobacterial Activity ◽  
Drug Tolerance ◽  
Host Immune System ◽  
Tissue Sections ◽  
Slow Growing

AbstractTuberculosis is a chronic disease that displays several features commonly associated with biofilm-associated infections: immune system evasion, antibiotic treatment failures, and recurrence of infection. However, although Mycobacterium tuberculosis (Mtb) can form cellulose-containing biofilms in vitro, it remains unclear whether biofilms are formed during infection in vivo. Here, we demonstrate the formation of Mtb biofilms in animal models of infection and in patients, and that biofilm formation can contribute to drug tolerance. First, we show that cellulose is also a structural component of the extracellular matrix of in vitro biofilms of fast and slow-growing nontuberculous mycobacteria. Then, we use cellulose as a biomarker to detect Mtb biofilms in the lungs of experimentally infected mice and non-human primates, as well as in lung tissue sections obtained from patients with tuberculosis. Mtb strains defective in biofilm formation are attenuated for survival in mice, suggesting that biofilms protect bacilli from the host immune system. Furthermore, the administration of nebulized cellulase enhances the antimycobacterial activity of isoniazid and rifampicin in infected mice, supporting a role for biofilms in phenotypic drug tolerance. Our findings thus indicate that Mtb biofilms are relevant to human tuberculosis.

scholarly journals CandidaBiofilms and the Host: Models and New Concepts for Eradication

2012 ◽  
Vol 2012 ◽  
pp. 1-16 ◽  
Author(s):  
Hélène Tournu ◽  
Patrick Van Dijck
Keyword(s):  
Immune System ◽  
High Throughput ◽  
Biofilm Formation ◽  
Host Immune System ◽  
Alternative Strategies ◽  
New Concepts ◽  
Potential Applications ◽  
Lock Therapy

Biofilms define mono- or multispecies communities embedded in a self-produced protective matrix, which is strongly attached to surfaces. They often are considered a general threat not only in industry but also in medicine. They constitute a permanent source of contamination, and they can disturb the proper usage of the material onto which they develop. This paper relates to some of the most recent approaches that have been elaborated to eradicateCandidabiofilms, based on the vast effort put in ever-improving models of biofilm formationin vitroandin vivo, including novel flow systems, high-throughput techniques and mucosal models. Mixed biofilms, sustaining antagonist or beneficial cooperation between species, and their interplay with the host immune system are also prevalent topics. Alternative strategies against biofilms include the lock therapy and immunotherapy approaches, and material coating and improvements. The host-biofilm interactions are also discussed, together with their potential applications inCandidabiofilm elimination.

scholarly journals Ambroxol Induces Autophagy and Potentiates Rifampin Antimycobacterial Activity

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
Seong Won Choi ◽  
Yuexi Gu ◽  
Ryan Scott Peters ◽  
Padmini Salgame ◽  
Jerrold J. Ellner ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Antimycobacterial Activity ◽  
Lead Compound ◽  
Content Type ◽  
Tuberculosis Model

ABSTRACT Host-directed therapy in tuberculosis is a potential adjunct to antibiotic chemotherapy directed at Mycobacterium tuberculosis. Ambroxol, a lead compound, emerged from a screen for autophagy-inducing drugs. At clinically relevant doses, ambroxol induced autophagy in vitro and in vivo and promoted mycobacterial killing in macrophages. Ambroxol also potentiated rifampin activity in a murine tuberculosis model.

scholarly journals The 8-Pyrrole-Benzothiazinones Are Noncovalent Inhibitors of DprE1 from Mycobacterium tuberculosis

2015 ◽  
Vol 59 (8) ◽  
pp. 4446-4452 ◽  
Author(s):  
Vadim Makarov ◽  
João Neres ◽  
Ruben C. Hartkoorn ◽  
Olga B. Ryabova ◽  
Elena Kazakova ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Nitro Group ◽  
Covalent Bond ◽  
Antimycobacterial Activity ◽  
Content Type ◽  
Sar Studies ◽  
Covalent Bond Formation

ABSTRACT8-Nitro-benzothiazinones (BTZs), such as BTZ043 and PBTZ169, inhibit decaprenylphosphoryl-β-d-ribose 2′-oxidase (DprE1) and display nanomolar bactericidal activity againstMycobacterium tuberculosisin vitro. Structure-activity relationship (SAR) studies revealed the 8-nitro group of the BTZ scaffold to be crucial for the mechanism of action, which involves formation of a semimercaptal bond with Cys387 in the active site of DprE1. To date, substitution of the 8-nitro group has led to extensive loss of antimycobacterial activity. Here, we report the synthesis and characterization of the pyrrole-benzothiazinones PyrBTZ01 and PyrBTZ02, non-nitro-benzothiazinones that retain significant antimycobacterial activity, with MICs of 0.16 μg/ml againstM. tuberculosis. These compounds inhibit DprE1 with 50% inhibitory concentration (IC50) values of <8 μM and present favorablein vitroabsorption-distribution-metabolism-excretion/toxicity (ADME/T) andin vivopharmacokinetic profiles. The most promising compound, PyrBTZ01, did not show efficacy in a mouse model of acute tuberculosis, suggesting that BTZ-mediated killing through DprE1 inhibition requires a combination of both covalent bond formation and compound potency.

scholarly journals Assessment of Mycobacterium tuberculosis Pantothenate Kinase Vulnerability through Target Knockdown and Mechanistically Diverse Inhibitors

2014 ◽  
Vol 58 (6) ◽  
pp. 3312-3326 ◽  
Author(s):  
B. K. Kishore Reddy ◽  
Sudhir Landge ◽  
Sudha Ravishankar ◽  
Vikas Patil ◽  
Vikas Shinde ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Present Report ◽  
Kinetic Studies ◽  
Antimycobacterial Activity ◽  
Type I ◽  
Pantothenate Kinase ◽  
Content Type ◽  
Rate Limiting Step

ABSTRACTPantothenate kinase (PanK) catalyzes the phosphorylation of pantothenate, the first committed and rate-limiting step toward coenzyme A (CoA) biosynthesis. In our earlier reports, we had established that the type I isoform encoded by thecoaAgene is an essential pantothenate kinase inMycobacterium tuberculosis, and this vital information was then exploited to screen large libraries for identification of mechanistically different classes of PanK inhibitors. The present report summarizes the synthesis and expansion efforts to understand the structure-activity relationships leading to the optimization of enzyme inhibition along with antimycobacterial activity. Additionally, we report the progression of two distinct classes of inhibitors, the triazoles, which are ATP competitors, and the biaryl acetic acids, with a mixed mode of inhibition. Cocrystallization studies provided evidence of these inhibitors binding to the enzyme. This was further substantiated with the biaryl acids having MIC against the wild-typeM. tuberculosisstrain and the subsequent establishment of a target link with an upshift in MIC in a strain overexpressing PanK. On the other hand, the ATP competitors had cellular activity only in aM. tuberculosisknockdown strain with reduced PanK expression levels. Additionally,in vitroandin vivosurvival kinetic studies performed with aM. tuberculosisPanK (MtPanK) knockdown strain indicated that the target levels have to be significantly reduced to bring in growth inhibition. The dual approaches employed here thus established the poor vulnerability of PanK inM. tuberculosis.

scholarly journals Antitumor and immunomodulatory activity of Inonotus obliquus

2017 ◽  
Vol 63 (2) ◽  
pp. 48-58 ◽  
Author(s):  
Justyna Staniszewska ◽  
Marcin Szymański ◽  
Ewa Ignatowicz
Keyword(s):  
Immune System ◽  
Tumor Cells ◽  
Good Alternative ◽  
Immunomodulatory Activity ◽  
Host Immune System ◽  
Protein Synthesis Inhibition ◽  
Inonotus Obliquus ◽  
Different Types

SummaryThe article presents the antitumor and immunomodulatory activity of compounds and extracts fromInonotus obliquus.Polysaccharides isolated from sclerotium have a direct antitumor effect due to protein synthesis inhibition in tumor cells. Polysaccharides derived from the mycelium function by activating the immune system. Due to the limited toxicity of these substances, both extracts as well as isolated and purified chemicals may be a good alternative to current chemotherapy and play a role in cancer prevention.In vitroexperiments have shown the inhibition of inflammation with the influence of action ofI. obliquusextracts; however,in vivoexperiments on animals implanted with tumor cells of different types have shown the activation of the host immune system. This led to decrease in tumor mass and prolonged survival. The immunomodulatory mechanism of action is complex and it seems that stimulation of macrophages and induction of apoptosis in cancer cells is of great importance.

scholarly journals Rescuing the Host Immune System by Targeting the Immune Evasion Complex ORF8-IRF3 in SARS-CoV-2 Infection with Natural Products Using Molecular Modeling Approaches

2021 ◽  
Vol 19 (1) ◽  
pp. 112
Author(s):  
Aqel Albutti
Keyword(s):  
Immune System ◽  
Immune Evasion ◽  
Simulation Analysis ◽  
Dynamic Properties ◽  
Natural Compounds ◽  
Host Immune System ◽  
Structural Dynamic ◽  
Novel Drugs

The perennial emergence of SARS-CoV-2 and its new variants causing upper respiratory complexities since December 2019 has aggravated the pandemic situation around the world. SARS-CoV-2 encodes several proteins among which ORF8 is a novel factor that is unique to SARS-CoV-2 only and is reported to help the virus in disease severity and immune evasion. ORF8-IRF3 complex induces endoplasmic reticulum stress, thus helps in the evasion of immune response. Consequently, targeting the ORF8-IRF3 complex is considered as a prime target for the discovery of novel drugs against SARS-CoV-2. In this regard, computational methods are of great interest to fast track the identification and development of novel drugs. Virtual screening of South African Natural Compounds Database (SANCDB), followed by docking and molecular dynamics (MD) simulation analysis, were performed to determine novel natural compounds. Computational molecular search and rescoring of the SANCDB database followed by induced-fit docking (IFD) protocol identified Quercetin 3-O-(6″-galloyl)-beta-D-galactopyranoside (SANC00850), Tribuloside (SANC01050), and Rutin (SANC00867) are the best scoring compounds. Structural-dynamic properties assessment revealed that these three compounds have stable dynamics, compactness, and a higher number of hydrogen bonds. For validation, we used MM/GBSA, in silico bioactivity estimation and dissociation constant (KD) approaches, which revealed that these compounds are the more potent inhibitors of the ORF8-IRF3 complex and would rescue the host immune system potentially. These compounds need further in vitro and in vivo validations to be used as therapeutics against SARS-CoV-2 to rescue the host immune system during COVID-19 infection.

scholarly journals Structure-Activity Relationships of Wollamide Cyclic Hexapeptides with Activity against Drug-Resistant and Intracellular Mycobacterium tuberculosis

2019 ◽  
Vol 63 (3) ◽  
Author(s):  
Zeinab G. Khalil ◽  
Timothy A. Hill ◽  
Luis M. De Leon Rodriguez ◽  
Rink-Jan Lohman ◽  
Huy N. Hoang ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Mammalian Cells ◽  
Antimycobacterial Activity ◽  
Drug Resistant ◽  
Amino Acid Residues ◽  
Content Type ◽  
Cyclic Hexapeptides ◽  
Rats And Mice

ABSTRACT Wollamides are cyclic hexapeptides, recently isolated from an Australian soil Streptomyces isolate, that exhibit promising in vitro antimycobacterial activity against Mycobacterium bovis Bacille Calmette Guérin without displaying cytotoxicity against a panel of mammalian cells. Here, we report the synthesis and antimycobacterial activity of 36 new synthetic wollamides, collated with all known synthetic and natural wollamides, to reveal structure characteristics responsible for in vitro growth-inhibitory activity against Mycobacterium tuberculosis (H37Rv, H37Ra, CDC1551, HN878, and HN353). The most potent antimycobacterial wollamides were those where residue VI d-Orn (wollamide B) was replaced by d-Arg (wollamide B1) or d-Lys (wollamide B2), with all activity being lost when residue VI was replaced by Gly, l-Arg, or l-Lys (wollamide B3). Substitution of other amino acid residues mainly reduced or ablated antimycobacterial activity. Significantly, whereas wollamide B2 was the most potent in restricting M. tuberculosis in vitro, wollamide B1 restricted M. tuberculosis intracellular burden in infected macrophages. Wollamide B1 synergized with pretomanid (PA-824) in inhibiting M. tuberculosis in vitro growth but did not antagonize prominent first- and second-line tuberculosis antibiotics. Furthermore, wollamide B1 exerted bactericidal activity against nonreplicating M. tuberculosis and impaired growth of multidrug- and extensively drug-resistant clinical isolates. In vivo pharmacokinetic profiles for wollamide B1 in rats and mice encourage further optimization of the wollamide pharmacophore for in vivo bioavailability. Collectively, these observations highlight the potential of the wollamide antimycobacterial pharmacophore.

scholarly journals Analysis of the intestinal microbiota in COVID-19 patients and its correlation with the inflammatory factor IL-18 and SARS-CoV-2-specific IgA

2020 ◽  
Author(s):  
Wanyin Tao ◽  
Shu Zhu ◽  
Guorong Zhang ◽  
Xiaofang Wang ◽  
Meng Guo ◽  
...  
Keyword(s):  
Immune System ◽  
Gastrointestinal Tract ◽  
Gut Microbiota ◽  
Disease Severity ◽  
Specific Cell ◽  
Host Immune System ◽  
Inflammatory Factor ◽  
Cytokine Storm

The current global COVID-19 pandemic is caused by beta coronavirus Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), which already infected over 10 million and caused 500 thousand deaths by June 2020. Overproduction of cytokines triggered by COVID-19 infection, known as "cytokine storm", is a highly risk factor associated with disease severity. However, how COVID-19 infection induce cytokine storm is still largely unknown. Accumulating in vitro and in vivo evidence suggests that gut is also susceptible to COVID19 infection: Human intestinal organoids, an in vitro model which mimic the specific cell type and spatial structure of the intestine, were susceptible to SARS-CoV2 infection; A significant fraction of patients reported gut symptoms; Viral RNA may persist for more than 30 days and infectious virus could be isolated in fecal samples. The gastrointestinal tract is the primary site of interaction between the host immune system with symbiotic and pathogenic microorganisms. The bacteria resident in our gastrointestinal tract, known as gut microbiota, is important to maintain the homeostasis of our immune system. While imbalance of gut microbiota, or dysbiosis, is associated with multiple inflammation diseases5. It's possible that SARS-CoV-2 infection may lead to alternation of gut microbiota thus worsen the host symptom. IL-18 is a proinflammatory cytokine produced multiple enteric cells, including intestinal epithelial cells (IECs), immune cells as well as enteric nervous system, and was shown to increase in the serum of COVID-19 patients. Immunoglobin A (IgA) is mainly produced in the mucosal surfaces, in humans 40-60mg kg-1 day-1 than all other immunoglobulin isotypes combined, and at least 80% of all plasma cells are located in the intestinal lamina propria. Recent study showed that SARS-CoV-2 specific IgA in the serum is positively correlate with the disease severity in COVID-19 patients11. Here we investigated the alterations of microbiota in COVID-19 patients, and its correlation with inflammatory factor IL-18 and SARS-CoV2 specific IgA.

scholarly journals MTS1338, a smallMycobacterium tuberculosisRNA, regulates transcriptional shifts consistent with bacterial adaptation for entering into dormancy and survival within host macrophages

2018 ◽  
Author(s):  
Elena G. Salina ◽  
Artem Grigorov ◽  
Yulia Skvortsova ◽  
Konstantin Majorov ◽  
Oksana Bychenko ◽  
...  
Keyword(s):  
Immune System ◽  
Ex Vivo ◽  
Host Immune System ◽  
Rna Seq ◽  
Bacterial Adaptation ◽  
Translational Activity ◽  
Non Coding Rna ◽  
Constitutive Overexpression

AbstractSmall non-coding RNAs play a significant role in bacterial adaptation to changing environmental conditions. We investigated the dynamics of expression of MTS1338, a small non-coding RNA ofMycobacterium tuberculosis, in the mouse modelin vivo, regulation of its expression in theex vivoinfected macrophages, and the consequences of its overexpression in bacterial cultures. Here we demonstrate that MTS1338 significantly contributes to host-pathogen interactions. Activation of the host immune system triggered NO-inducible up-regulation of MTS1338 in macrophage-engulfed mycobacteria. Constitutive overexpression of MTS1338 in cultured mycobacteria improved their survivalin vitrounder low pH conditions. MTS1338 up-regulation launched a spectrum of shifts in the transcriptome profile similar to those reported forM. tuberculosisadaptation to hostile intra-macrophage environment. Using the RNA-seq approach, we demonstrate that gene expression changes accompanying MTS1338 overexpression indicate reduction in translational activity and bacterial growth, which is consistent with entering the dormant state. Taken together, our results suggest a direct involvement on this sRNA in the interplay between mycobacteria and the host immune system during infectious process.

scholarly journals Schistosomes alter expression of immunomodulatory gene products following in vivo praziquantel exposure

2020 ◽  
Author(s):  
Paul McCusker ◽  
Claudia M. Rohr ◽  
John D. Chan
Keyword(s):  
Immune System ◽  
Immune Evasion ◽  
Host Immune System ◽  
Gene Products ◽  
Response To Chemotherapy ◽  
Kunitz Type ◽  
Insight Into ◽  
Immunomodulatory Gene

AbstractControl of the neglected tropical disease schistosomiasis relies almost entirely on praziquantel (PZQ) monotherapy. How PZQ clears parasite infections remains poorly understood. Many studies have examined the effects of PZQ on worms cultured in vitro, observing outcomes such as muscle contraction. However, conditions worms are exposed to in vivo may vary considerably from in vitro experiments given the short half-life of PZQ and the importance of host immune system engagement for drug efficacy in animal models. Here, we investigated the effects of in vivo PZQ exposure on Schistosoma mansoni. Measurement of pro-apoptotic caspase activation revealed that worm death occurs only after parasites shift from the mesenteric vasculature to the liver, peaking 24 hours after drug treatment. This indicates that PZQ is not directly schistocidal, since the drug’s half-life is ∼2 hours, and focuses attention on parasite interactions with the host immune system following the shift of worms to the liver. RNA-Seq of worms harvested from mouse livers following sub-lethal PZQ treatment revealed drug-evoked changes in the expression of putative immunomodulatory and anticoagulant gene products. Several of these gene products localized to the schistosome esophagus and may be secreted into the host circulation. These include several Kunitz-type protease inhibitors, which are also found in the secretomes of other blood feeding animals. These transcriptional changes may reflect mechanisms of parasite immune-evasion in response to chemotherapy, given the role of complement-mediated attack and the host innate / humoral immune response in parasite elimination. One of these isoforms, SmKI-1, has been shown to exhibit immunomodulatory and anti-coagulant properties. These data provide insight into the effect of in vivo PZQ exposure on S. mansoni, and the transcriptional response of parasites to the stress of chemotherapy.Author SummaryThe disease schistosomiasis is caused by parasitic worms that live within the circulatory system. While this disease infects over 200 million people worldwide, treatment relies almost entirely on one drug, praziquantel, whose mechanism is poorly understood. In this study, we analyzed the effects of praziquantel treatment on the gene expression of parasites harvested from mice treated with praziquantel chemotherapy. Despite the rapid action of the drug on worms in vitro, we found that key outcomes in vivo (measurement of cell death and changes in gene expression) occurred relatively late (12+ hours after drug administration). We found that worms increased the expression of immunomodulatory gene products in response to praziquantel, including a Kunitz-type protease inhibitor that localized to the worm esophagus and may be secreted to the external host environment. These are an intriguing class of proteins, because they display anti-coagulant and immunomodulatory properties. Up-regulation of these gene products may reflect a parasite mechanism of immune-evasion in response to chemotherapy. This research provides insight into the mechanism of praziquantel by observing the effect of this drug on worms within the context of the host immune system.

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