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1.
Molecules ; 26(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34361751

RESUMO

Species of Mycobacteriaceae cause disease in animals and humans, including tuberculosis and leprosy. Individuals infected with organisms in the Mycobacterium tuberculosis complex (MTBC) or non-tuberculous mycobacteria (NTM) may present identical symptoms, however the treatment for each can be different. Although the NTM infection is considered less vital due to the chronicity of the disease and the infrequency of occurrence in healthy populations, diagnosis and differentiation among Mycobacterium species currently require culture isolation, which can take several weeks. The use of volatile organic compounds (VOCs) is a promising approach for species identification and in recent years has shown promise for use in the rapid analysis of both in vitro cultures as well as ex vivo diagnosis using breath or sputum. The aim of this contribution is to analyze VOCs in the culture headspace of seven different species of mycobacteria and to define the volatilome profiles that are discriminant for each species. For the pre-concentration of VOCs, solid-phase micro-extraction (SPME) was employed and samples were subsequently analyzed using gas chromatography-quadrupole mass spectrometry (GC-qMS). A machine learning approach was applied for the selection of the 13 discriminatory features, which might represent clinically translatable bacterial biomarkers.


Assuntos
Metaboloma , Mycobacterium abscessus/química , Complexo Mycobacterium avium/química , Mycobacterium avium/química , Mycobacterium bovis/química , Mycobacterium/química , Compostos Orgânicos Voláteis/isolamento & purificação , Biomarcadores/análise , Cromatografia Gasosa-Espectrometria de Massas/métodos , Aprendizado de Máquina/estatística & dados numéricos , Mycobacterium/metabolismo , Mycobacterium abscessus/metabolismo , Mycobacterium avium/metabolismo , Complexo Mycobacterium avium/metabolismo , Mycobacterium bovis/metabolismo , Análise de Componente Principal , Microextração em Fase Sólida , Compostos Orgânicos Voláteis/classificação , Compostos Orgânicos Voláteis/metabolismo
2.
Int J Mol Sci ; 22(14)2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34299217

RESUMO

The mycobacterial cell wall is composed of large amounts of lipids with varying moieties. Some mycobacteria species hijack host cells and promote lipid droplet accumulation to build the cellular environment essential for their intracellular survival. Thus, lipids are thought to be important for mycobacteria survival as well as for the invasion, parasitization, and proliferation within host cells. However, their physiological roles have not been fully elucidated. Recent studies have revealed that mycobacteria modulate the peroxisome proliferator-activated receptor (PPAR) signaling and utilize host-derived triacylglycerol (TAG) and cholesterol as both nutrient sources and evasion from the host immune system. In this review, we discuss recent findings that describe the activation of PPARs by mycobacterial infections and their role in determining the fate of bacilli by inducing lipid metabolism, anti-inflammatory function, and autophagy.


Assuntos
Infecções por Mycobacterium/microbiologia , Mycobacterium/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Animais , Autofagia/fisiologia , Colesterol/metabolismo , Humanos , Metabolismo dos Lipídeos , Mycobacterium/crescimento & desenvolvimento , Mycobacterium/imunologia , Infecções por Mycobacterium/imunologia , Infecções por Mycobacterium/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/genética , Transdução de Sinais
4.
Molecules ; 25(3)2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32046221

RESUMO

Therapeutic treatment options for opportunistic non-tuberculous mycobacterial (NTM) infection and/or serious mycobacterial infections such as tuberculosis (TB) and leprosy are limited due to the spread of antimicrobial resistance mechanism. Plant-derived natural compounds as prospective efflux pump inhibitors may present a promising adjunct to conventional chemotherapy by enhancing mycobacterial susceptibility to antibiotics. This study served to evaluate the antimicrobial and resistance-modifying profile of a range of plant-derived flavonoids against the mycobacterial model strains: M. smegmatis, M. aurum, and M. bovis BCG. The minimum inhibitory concentrations (MICs) of the compounds against the mycobacterial strains were determined using both agar dilution and broth dilution assays, while their efflux inhibitory activity was investigated via an ethidium bromide-based fluorometric assay. All compounds were screened for their synergistic effects with ethidium bromide (EtBr) and rifampicin (RIF) against M. smegmatis. Skullcapflavone II (5,2'-dihydroxy-6,7,8,6'-tetramethoxyflavone, 1) exerted potent antimicrobial activity against M. aurum and M. bovis BCG and considerably increased the susceptibility of M. smegmatis to EtBr and RIF. Nobiletin (5,6,7,8,3',4'-hexamethoxyflavone, 2) was determined to be the most potent efflux-inhibitor in M. aurum and M. smegmatis. However, a connection between strong modulatory and putative efflux activity of the compounds could not be observed. Nevertheless, the results highlight two polymethoxyflavones, skullcapflavone II and nobiletin, with potent antimycobacterial and antibiotic resistance modulating activities as valuable adjuvants in anti-mycobacterial therapies.


Assuntos
Anti-Infecciosos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Flavonoides/farmacologia , Mycobacterium/efeitos dos fármacos , Proteínas de Bactérias/metabolismo , Transporte Biológico/efeitos dos fármacos , Etídio/química , Proteínas de Membrana Transportadoras/metabolismo , Testes de Sensibilidade Microbiana/métodos , Mycobacterium/metabolismo , Infecções por Mycobacterium/tratamento farmacológico , Rifampina/farmacologia
5.
Transcription ; 11(2): 53-65, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31880185

RESUMO

Recent biophysical studies of mycobacterial transcription have shed new light on this fundamental process in a group of bacteria that includes deadly pathogens such as Mycobacterium tuberculosis (Mtb), Mycobacterium abscessus (Mab), Mycobacterium leprae (Mlp), as well as the nonpathogenic Mycobacterium smegmatis (Msm). Most of the research has focused on Mtb, the causative agent of tuberculosis (TB), which remains one of the top ten causes of death globally. The enzyme RNA polymerase (RNAP) is responsible for all bacterial transcription and is a target for one of the crucial antibiotics used for TB treatment, rifampicin (Rif). Here, we summarize recent biophysical studies of mycobacterial RNAP that have advanced our understanding of the basic process of transcription, have revealed novel paradigms for regulation, and thus have provided critical information required for developing new antibiotics against this deadly disease.


Assuntos
Mycobacterium/genética , Transcrição Genética/genética , Mycobacterium/metabolismo , RNA Polimerase Dependente de RNA/genética , RNA Polimerase Dependente de RNA/metabolismo , Tuberculose/microbiologia
6.
Microbiol Spectr ; 7(2)2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-31025625

RESUMO

How do mycobacteria divide? Cell division has been studied extensively in the model rod-shaped bacteria Escherichia coli and Bacillus subtilis, but much less is understood about cell division in mycobacteria, a genus that includes the major human pathogens M. tuberculosis and M. leprae. In general, bacterial cell division requires the concerted effort of many proteins in both space and time to elongate the cell, replicate and segregate the chromosome, and construct and destruct the septum - processes which result in the creation of two new daughter cells. Here, we describe these distinct stages of cell division in B. subtilis and follow with the current knowledge in mycobacteria. As will become apparent, there are many differences between mycobacteria and B. subtilis in terms of both the broad outline of cell division and the molecular details. So, while the fundamental challenge of spatially and temporally organizing cell division is shared between these rod-shaped bacteria, they have solved these challenges in often vastly different ways.


Assuntos
Divisão Celular/fisiologia , Mycobacterium/crescimento & desenvolvimento , Mycobacterium/metabolismo , Bacillus subtilis/genética , Bacillus subtilis/crescimento & desenvolvimento , Bacillus subtilis/metabolismo , Proteínas de Bactérias/metabolismo , Proteínas de Ciclo Celular/metabolismo , Divisão Celular/genética , Parede Celular , Replicação do DNA , Escherichia coli/genética , Escherichia coli/crescimento & desenvolvimento , Escherichia coli/metabolismo , Mycobacterium/genética , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/crescimento & desenvolvimento , Mycobacterium tuberculosis/metabolismo
7.
Int Immunopharmacol ; 70: 408-416, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30856391

RESUMO

Very few adjuvants inducing Th1 immune response have been developed and are under clinical investigation. Hence, there is the need to find an adjuvant that elicits strong Th1 immune response which should be safe when injected in the host along with vaccines. Mycobacterium indicus pranii (MIP), a non-pathogenic vaccine candidate, has shown strong immunomodulatory activity in leprosy/tuberculosis/cancer and in genital warts patients where its administration shifted the host immune response towards Th1 type. These findings prompted us to study the components of MIP in detail for their Th1 inducing property. Since mycobacterial cell wall is very rich in immunostimulatory components and is known to play important role in immune modulation, we investigated the activity of MIP cell wall using Ovalbumin antigen (OVA) as model antigen. 'Whole cell wall' (CW) and 'aqueous soluble cell wall fractions' (ACW) induced significant Th1 immune response while 'cell wall skeleton' (CWS) induced strong Th2 type of immune response. Finally, functional activity of fractions having Th1 inducing activity was evaluated in mouse model of melanoma. CW demonstrated significant anti-tumor activity similar to whole MIP. Anti-tumor activity of CW could be correlated with enhanced tumor antigen specific Th1 immune response observed in tumor draining lymph nodes.


Assuntos
Parede Celular/metabolismo , Melanoma/imunologia , Mycobacterium/metabolismo , Células Th1/imunologia , Células Th2/imunologia , Animais , Antígenos de Neoplasias/imunologia , Parede Celular/imunologia , Humanos , Imunomodulação , Ativação Linfocitária , Melanoma/terapia , Melanoma Experimental , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Experimentais , Equilíbrio Th1-Th2
8.
Emerg Microbes Infect ; 8(1): 109-118, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30866765

RESUMO

Of the more than 190 distinct species of Mycobacterium genus, many are economically and clinically important pathogens of humans or animals. Among those mycobacteria that infect humans, three species namely Mycobacterium tuberculosis (causative agent of tuberculosis), Mycobacterium leprae (causative agent of leprosy) and Mycobacterium abscessus (causative agent of chronic pulmonary infections) pose concern to global public health. Although antibiotics have been successfully developed to combat each of these, the emergence of drug-resistant strains is an increasing challenge for treatment and drug discovery. Here we describe the impact of the rapid expansion of genome sequencing and genome/pathway annotations that have greatly improved the progress of structure-guided drug discovery. We focus on the applications of comparative genomics, metabolomics, evolutionary bioinformatics and structural proteomics to identify potential drug targets. The opportunities and challenges for the design of drugs for M. tuberculosis, M. leprae and M. abscessus to combat resistance are discussed.


Assuntos
Proteínas de Bactérias/química , Biologia Computacional/métodos , Mycobacterium/genética , Análise de Sequência de DNA/métodos , Animais , Proteínas de Bactérias/metabolismo , Descoberta de Drogas , Farmacorresistência Bacteriana , Genoma Bacteriano , Humanos , Anotação de Sequência Molecular , Mycobacterium/metabolismo , Mycobacterium abscessus/genética , Mycobacterium abscessus/metabolismo , Mycobacterium leprae/genética , Mycobacterium leprae/metabolismo , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/metabolismo , Conformação Proteica , Proteômica
9.
Mol Microbiol ; 110(5): 663-676, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30179278

RESUMO

The WhiB-like (Wbl) family of proteins are exclusively found in Actinobacteria. Wbls have been shown to play key roles in virulence and antibiotic resistance in Mycobacteria and Corynebacteria, reflecting their importance during infection by the human pathogens Mycobacterium tuberculosis, Mycobacterium leprae and Corynebacterium diphtheriae. In the antibiotic-producing Streptomyces, several Wbls have important roles in the regulation of morphological differentiation, including WhiB, a protein that controls the initiation of sporulation septation and the founding member of the Wbl family. In recent years, genome sequencing has revealed the prevalence of Wbl paralogues in species throughout the Actinobacteria. Wbl proteins are small (generally ~80-140 residues) and each contains four invariant cysteine residues that bind an O2 - and NO-sensitive [4Fe-4S] cluster, raising the question as to how they can maintain distinct cellular functions within a given species. Despite their discovery over 25 years ago, the Wbl protein family has largely remained enigmatic. Here I summarise recent research in Mycobacteria, Corynebacteria and Streptomyces that sheds light on the biochemical function of Wbls as transcription factors and as potential sensors of O2 and NO. I suggest that Wbl evolution has created diversity in protein-protein interactions, [4Fe-4S] cluster-sensitivity and the ability to bind DNA.


Assuntos
Proteínas de Bactérias/metabolismo , Corynebacterium/metabolismo , Mycobacterium/metabolismo , Streptomyces/metabolismo , Fatores de Transcrição/metabolismo , Proteínas de Bactérias/genética , Corynebacterium/genética , Regulação Bacteriana da Expressão Gênica , Mycobacterium/genética , Streptomyces/genética , Fatores de Transcrição/genética
11.
J Biol Chem ; 293(14): 5172-5184, 2018 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-29472294

RESUMO

Mycolic acids are the hallmark of the cell envelope in mycobacteria, which include the important human pathogens Mycobacterium tuberculosis and Mycobacterium leprae Mycolic acids are very long C60-C90 α-alkyl ß-hydroxy fatty acids having a variety of functional groups on their hydrocarbon chain that define several mycolate types. Mycobacteria also produce an unusually large number of putative epoxide hydrolases, but the physiological functions of these enzymes are still unclear. Here, we report that the mycobacterial epoxide hydrolase EphD is involved in mycolic acid metabolism. We found that orthologs of EphD from M. tuberculosis and M. smegmatis are functional epoxide hydrolases, cleaving a lipophilic substrate, 9,10-cis-epoxystearic acid, in vitro and forming a vicinal diol. The results of EphD overproduction in M. smegmatis and M. bovis BCG Δhma strains producing epoxymycolic acids indicated that EphD is involved in the metabolism of these forms of mycolates in both fast- and slow-growing mycobacteria. Moreover, using MALDI-TOF-MS and 1H NMR spectroscopy of mycolic acids and lipids isolated from EphD-overproducing M. smegmatis, we identified new oxygenated mycolic acid species that accumulated during epoxymycolate depletion. Disruption of the ephD gene in M. tuberculosis specifically impaired the synthesis of ketomycolates and caused accumulation of their precursor, hydroxymycolate, indicating either direct or indirect involvement of EphD in ketomycolate biosynthesis. Our results clearly indicate that EphD plays a role in metabolism of oxygenated mycolic acids in mycobacteria.


Assuntos
Epóxido Hidrolases/metabolismo , Ácidos Micólicos/metabolismo , Parede Celular/metabolismo , Ácidos Graxos/metabolismo , Metabolismo dos Lipídeos/fisiologia , Lipídeos/fisiologia , Espectrometria de Massas/métodos , Mycobacterium/metabolismo , Mycobacterium smegmatis/metabolismo , Mycobacterium tuberculosis/metabolismo
12.
Biochim Biophys Acta ; 1861(1): 60-67, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26515252

RESUMO

Diseases including tuberculosis and leprosy are caused by species of the Mycobacterium genus and are a huge burden on global health, aggravated by the emergence of drug resistant strains. Mycobacteria have a high lipid content and complex lipid profile including several unique classes of lipid. Recent years have seen a growth in research focused on lipid structures, metabolism and biological functions driven by advances in mass spectrometry techniques and instrumentation, particularly the use of electrospray ionization. Here we review the contributions of lipidomics towards the advancement of our knowledge of lipid metabolism in mycobacterial species.


Assuntos
Metabolismo dos Lipídeos , Mycobacterium/metabolismo , Biologia Computacional , Glicolipídeos/metabolismo , Lipídeos/biossíntese , Espectrometria de Massas , Ácidos Micólicos/metabolismo , Triglicerídeos/metabolismo
13.
Int J Mycobacteriol ; 4(3): 207-16, 2015 09.
Artigo em Inglês | MEDLINE | ID: mdl-27649868

RESUMO

Mycobacterium aurum (M. aurum) is an environmental mycobacteria that has previously been used in studies of anti-mycobacterial drugs due to its fast growth rate and low pathogenicity. The M. aurum genome has been sequenced and assembled into 46 contigs, with a total length of 6.02Mb containing 5684 annotated protein-coding genes. A phylogenetic analysis using whole genome alignments positioned M. aurum close to Mycobacterium vaccae and Mycobacterium vanbaalenii, within a clade related to fast-growing mycobacteria. Large-scale genomic rearrangements were identified by comparing the M. aurum genome to those of Mycobacterium tuberculosis and Mycobacterium leprae. M. aurum orthologous genes implicated in resistance to anti-tuberculosis drugs in M. tuberculosis were observed. The sequence identity at the DNA level varied from 68.6% for pncA (pyrazinamide drug-related) to 96.2% for rrs (streptomycin, capreomycin). We observed two homologous genes encoding the catalase-peroxidase enzyme (katG) that is associated with resistance to isoniazid. Similarly, two embB homologues were identified in the M. aurum genome. In addition to describing for the first time the genome of M. aurum, this work provides a resource to aid the use of M. aurum in studies to develop improved drugs for the pathogenic mycobacteria M. tuberculosis and M. leprae.


Assuntos
Antituberculosos/farmacologia , Genoma Bacteriano/genética , Mycobacterium leprae/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium/genética , Proteínas de Bactérias/metabolismo , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Resistência Microbiana a Medicamentos/efeitos dos fármacos , Resistência Microbiana a Medicamentos/genética , Testes de Sensibilidade Microbiana , Mycobacterium/efeitos dos fármacos , Mycobacterium/enzimologia , Mycobacterium/metabolismo , Pentosiltransferases/metabolismo , Peroxidases/metabolismo , Filogenia
14.
Protein Sci ; 24(1): 1-10, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25303009

RESUMO

Protein production using recombinant DNA technology has a fundamental impact on our understanding of biology through providing proteins for structural and functional studies. Escherichia coli (E. coli) has been traditionally used as the default expression host to over-express and purify proteins from many different organisms. E. coli does, however, have known shortcomings for obtaining soluble, properly folded proteins suitable for downstream studies. These shortcomings are even more pronounced for the mycobacterial pathogen Mycobacterium tuberculosis, the bacterium that causes tuberculosis, with typically only one third of proteins expressed in E. coli produced as soluble proteins. Mycobacterium smegmatis (M. smegmatis) is a closely related and non-pathogenic species that has been successfully used as an expression host for production of proteins from various mycobacterial species. In this review, we describe the early attempts to produce mycobacterial proteins in alternative expression hosts and then focus on available expression systems in M. smegmatis. The advantages of using M. smegmatis as an expression host, its application in structural biology and some practical aspects of protein production are also discussed. M. smegmatis provides an effective expression platform for enhanced understanding of mycobacterial biology and pathogenesis and for developing novel and better therapeutics and diagnostics.


Assuntos
Proteínas de Bactérias/genética , Clonagem Molecular/métodos , Mycobacterium smegmatis/genética , Proteínas Recombinantes/genética , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Vetores Genéticos/genética , Modelos Moleculares , Mycobacterium/química , Mycobacterium/genética , Mycobacterium/metabolismo , Mycobacterium smegmatis/química , Mycobacterium smegmatis/metabolismo , Processamento de Proteína Pós-Traducional , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo
15.
mBio ; 5(6): e02020, 2014 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-25370496

RESUMO

UNLABELLED: Mycobacterial evolution involves various processes, such as genome reduction, gene cooption, and critical gene acquisition. Our comparative genome size analysis of 44 mycobacterial genomes revealed that the nonpathogenic (NP) genomes were bigger than those of opportunistic (OP) or totally pathogenic (TP) mycobacteria, with the TP genomes being smaller yet variable in size--their genomic plasticity reflected their ability to evolve and survive under various environmental conditions. From the 44 mycobacterial species, 13 species, representing TP, OP, and NP, were selected for genomic-relatedness analyses. Analysis of homologous protein-coding genes shared between Mycobacterium indicus pranii (NP), Mycobacterium intracellulare ATCC 13950 (OP), and Mycobacterium tuberculosis H37Rv (TP) revealed that 4,995 (i.e., ~95%) M. indicaus pranii proteins have homology with M. intracellulare, whereas the homologies among M. indicus pranii, M. intracellulare ATCC 13950, and M. tuberculosis H37Rv were significantly lower. A total of 4,153 (~79%) M. indicus pranii proteins and 4,093 (~79%) M. intracellulare ATCC 13950 proteins exhibited homology with the M. tuberculosis H37Rv proteome, while 3,301 (~82%) and 3,295 (~82%) M. tuberculosis H37Rv proteins showed homology with M. indicus pranii and M. intracellulare ATCC 13950 proteomes, respectively. Comparative metabolic pathway analyses of TP/OP/NP mycobacteria showed enzymatic plasticity between M. indicus pranii (NP) and M. intracellulare ATCC 13950 (OP), Mycobacterium avium 104 (OP), and M. tuberculosis H37Rv (TP). Mycobacterium tuberculosis seems to have acquired novel alternate pathways with possible roles in metabolism, host-pathogen interactions, virulence, and intracellular survival, and by implication some of these could be potential drug targets. IMPORTANCE: The complete sequence analysis of Mycobacterium indicus pranii, a novel species of Mycobacterium shown earlier to have strong immunomodulatory properties and currently in use for the treatment of leprosy, places it evolutionarily at the point of transition to pathogenicity. With the purpose of establishing the importance of M. indicus pranii in providing insight into the virulence mechanism of tuberculous and nontuberculous mycobacteria, we carried out comparative genomic and proteomic analyses of 44 mycobacterial species representing nonpathogenic (NP), opportunistic (OP), and totally pathogenic (TP) mycobacteria. Our results clearly placed M. indicus pranii as an ancestor of the M. avium complex. Analyses of comparative metabolic pathways between M. indicus pranii (NP), M. tuberculosis (TP), and M. intracellulare (OP) pointed to the presence of novel alternative pathways in M. tuberculosis with implications for pathogenesis and survival in the human host and identification of new drug targets.


Assuntos
Adaptação Biológica , Adaptação Fisiológica , Microbiologia Ambiental , Variação Genética , Redes e Vias Metabólicas/genética , Mycobacterium/genética , Tuberculose/microbiologia , Proteínas de Bactérias/genética , Análise por Conglomerados , Evolução Molecular , Genoma Bacteriano , Humanos , Mycobacterium/metabolismo , Mycobacterium/patogenicidade , Filogenia , Homologia de Sequência de Aminoácidos
16.
Proc Natl Acad Sci U S A ; 111(37): 13451-6, 2014 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-25197060

RESUMO

Inflammatory diseases are characterized by dysregulated cytokine production. Altered functions for most risk loci, including the inflammatory bowel disease and leprosy-associated tumor necrosis factor ligand superfamily member 15 (TNFSF15) region, are unclear. Regulation of pattern-recognition-receptor (PRR)-induced signaling and cytokines is crucial for immune homeostasis; TNFSF15:death receptor 3 (DR3) contributions to PRR responses have not been described. We found that human macrophages expressed DR3 and that TNFSF15:DR3 interactions were critical for amplifying PRR-initiated MAPK/NF-κB/PI3K signaling and cytokine secretion in macrophages. Mechanisms mediating TNFSF15:DR3 contributions to PRR outcomes included TACE-induced TNFSF15 cleavage to soluble TNFSF15; soluble TNFSF15 then led to TRADD/FADD/MALT-1- and caspase-8-mediated autocrine IL-1 secretion. Notably, TNFSF15 treatment also induced cytokine secretion through a caspase-8-dependent pathway in intestinal myeloid cells. Importantly, rs6478108 A disease risk-carrier macrophages demonstrated increased TNFSF15 expression and PRR-induced signaling and cytokines. Taken together, TNFSF15:DR3 interactions amplify PRR-induced signaling and cytokines, and the rs6478108 TNFSF15 disease-risk polymorphism results in a gain of function.


Assuntos
Caspase 8/metabolismo , Predisposição Genética para Doença , Interleucina-1/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Receptores de Reconhecimento de Padrão/metabolismo , Transdução de Sinais , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Proteínas ADAM/metabolismo , Proteína ADAM17 , Acetilmuramil-Alanil-Isoglutamina/farmacologia , Células Cultivadas , Humanos , Ligantes , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Mycobacterium/metabolismo , Células Mieloides/efeitos dos fármacos , Células Mieloides/metabolismo , NF-kappa B/metabolismo , Proteína Adaptadora de Sinalização NOD2/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Membro 25 de Receptores de Fatores de Necrose Tumoral/metabolismo , Transdução de Sinais/efeitos dos fármacos , Solubilidade , Inibidor Tecidual de Metaloproteinase-3/metabolismo
17.
Postepy Hig Med Dosw (Online) ; 68: 350-8, 2014 Apr 04.
Artigo em Polonês | MEDLINE | ID: mdl-24864086

RESUMO

Mycolic acids are one of the basic structural elements of the cell wall of bacteria from Corynebacterineae suborder. These compounds are long-chain α-hydroxy ß-alkyl fatty acids with two hydrocarbon chains: longer meromycolic and shorter α-chain meromycolic α-chain. The genus Mycobacterium is characterized by the presence of mycolic acids in length from 60 to 90 carbon atoms having a fully saturated α-chain with a defined length of 22, 24 or 26 carbon atoms. Current research indicates that not only the presence of mycolic acids in the cell wall of mycobacteria is essential for the virulence of mycobacteria. It is proved that the relationship between different types of mycolic acids, their length and the degree of cyclopropanation may vary depending on the stage of infection and mycobacterial culture conditions. At the same time it has been shown that some mycolic acid types are crucial for biofilm formation, antimycobacterial drug resistance or interactions with the immune system. Recent studies also indicate that analysis of mycolic acid profiles could be an alternative to conventional methods of diagnosis of diseases such as tuberculosis, leprosy or mycobacteriosis.


Assuntos
Parede Celular/metabolismo , Mycobacterium/isolamento & purificação , Mycobacterium/metabolismo , Ácidos Micólicos/metabolismo , Biofilmes/crescimento & desenvolvimento , Ácidos Graxos/metabolismo , Mycobacterium/química , Ácidos Micólicos/análise , Virulência/fisiologia
18.
Chem Biol ; 21(1): 67-85, 2014 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-24374164

RESUMO

Mycolic acids are major and specific lipid components of the mycobacterial cell envelope and are essential for the survival of members of the genus Mycobacterium that contains the causative agents of both tuberculosis and leprosy. In the alarming context of the emergence of multidrug-resistant, extremely drug-resistant, and totally drug-resistant tuberculosis, understanding the biosynthesis of these critical determinants of the mycobacterial physiology is an important goal to achieve, because it may open an avenue for the development of novel antimycobacterial agents. This review focuses on the chemistry, structures, and known inhibitors of mycolic acids and describes progress in deciphering the mycolic acid biosynthetic pathway. The functional and key biological roles of these molecules are also discussed, providing a historical perspective in this dynamic area.


Assuntos
Ácidos Micólicos/química , Ácidos Micólicos/metabolismo , Antituberculosos/farmacologia , Humanos , Conformação Molecular , Mycobacterium/química , Mycobacterium/efeitos dos fármacos , Mycobacterium/metabolismo , Ácidos Micólicos/antagonistas & inibidores , Ácidos Micólicos/imunologia , Virulência
19.
Chembiochem ; 14(16): 2153-9, 2013 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-24115598

RESUMO

Phenolic glycolipids (PGLs) are virulence factors present in the cell walls of many pathogenic mycobacteria. PGLs have been implicated in various aspects of mycobacterial disease, but there are limited structure-activity data available for these molecules. We report here the preparation of seven synthetic PGL analogues, differing from the native compounds in the replacement of the complex phenolic lipid moiety with a p-methoxyphenyl group. The ability of these compounds to stimulate or inhibit the production of cytokines (TNF-α, IL-1ß, IL-6, MCP-1) and nitric oxide (NO) was then evaluated by ELISA-based assays. None of the compounds stimulated the production of these biological signalling molecules. In contrast, they each displayed concentration-dependent inhibitory activity, related to the methylation pattern of the molecule and mediated by Toll-like receptor 2. Additional studies revealed that native PGL-I from Mycobacterium leprae and a synthetic PGL-I analogue containing a simplified lipid domain had enhanced inhibitory activities relative to the corresponding analogues containing the p-methoxyphenyl aglycone; however, the natural lipid phenolthiocerol was only weakly active. These studies reveal that synthetic molecules of this type can be used as probes for PGL function. Moreover, their ease of synthesis relative to the natural glycolipids, as well as their more favourable aqueous solubility, should allow for more thorough structure-activity relationship studies.


Assuntos
Citocinas/metabolismo , Glicolipídeos/química , Glicolipídeos/farmacologia , Macrófagos/efeitos dos fármacos , Mycobacterium/metabolismo , Receptor 2 Toll-Like/metabolismo , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Linhagem Celular , Glicolipídeos/síntese química , Humanos , Macrófagos/citologia , Macrófagos/metabolismo , Óxido Nítrico/metabolismo , Fenóis/química , Relação Estrutura-Atividade
20.
Adv Microb Physiol ; 63: 147-94, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24054797

RESUMO

The genus Mycobacterium is comprised of Gram-positive bacteria occupying a wide range of natural habitats and includes species that range from severe intracellular pathogens to economically useful and harmless microbes. The recent upsurge in the availability of microbial genome data has shown that genes encoding haemoglobin-like proteins are ubiquitous among Mycobacteria and that multiple haemoglobins (Hbs) of different classes may be present in pathogenic and non-pathogenic species. The occurrence of truncated haemoglobins (trHbs) and flavohaemoglobins (flavoHbs) showing distinct haem active site structures and ligand-binding properties suggests that these Hbs may be playing diverse functions in the cellular metabolism of Mycobacteria. TrHbs and flavoHbs from some of the severe human pathogens such as Mycobacterium tuberculosis and Mycobacterium leprae have been studied recently and their roles in effective detoxification of reactive nitrogen and oxygen species, electron cycling, modulation of redox state of the cell and facilitation of aerobic respiration have been proposed. This multiplicity in the function of Hbs may aid these pathogens to cope with various environmental stresses and survive during their intracellular regime. This chapter provides recent updates on genomic, structural and functional aspects of Mycobacterial Hbs to address their role in Mycobacteria.


Assuntos
Proteínas de Bactérias/metabolismo , Hemeproteínas/metabolismo , Mycobacterium/metabolismo , Hemoglobinas Truncadas/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Biotransformação , Hemeproteínas/química , Hemeproteínas/genética , Redes e Vias Metabólicas , Modelos Moleculares , Mycobacterium/química , Mycobacterium/genética , Óxido Nítrico/metabolismo , Óxido Nítrico/toxicidade , Oxirredução , Oxigênio/metabolismo , Oxigênio/toxicidade , Conformação Proteica , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Nitrogênio/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Espécies Reativas de Oxigênio/toxicidade , Hemoglobinas Truncadas/química , Hemoglobinas Truncadas/genética
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