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1.
J Bacteriol ; 195(2): 389-98, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23161027

RESUMEN

The Sinorhizobium meliloti BacA ABC transporter protein plays an important role in its nodulating symbiosis with the legume alfalfa (Medicago sativa). The Mycobacterium tuberculosis BacA homolog was found to be important for the maintenance of chronic murine infections, yet its in vivo function is unknown. In the legume plant as well as in the mammalian host, bacteria encounter host antimicrobial peptides (AMPs). We found that the M. tuberculosis BacA protein was able to partially complement the symbiotic defect of an S. meliloti BacA-deficient mutant on alfalfa plants and to protect this mutant in vitro from the antimicrobial activity of a synthetic legume peptide, NCR247, and a recombinant human ß-defensin 2 (HBD2). This finding was also confirmed using an M. tuberculosis insertion mutant. Furthermore, M. tuberculosis BacA-mediated protection of the legume symbiont S. meliloti against legume defensins as well as HBD2 is dependent on its attached ATPase domain. In addition, we show that M. tuberculosis BacA mediates peptide uptake of the truncated bovine AMP, Bac7(1-16). This process required a functional ATPase domain. We therefore suggest that M. tuberculosis BacA is important for the transport of peptides across the cytoplasmic membrane and is part of a complete ABC transporter. Hence, BacA-mediated protection against host AMPs might be important for the maintenance of latent infections.


Asunto(s)
Proteínas Bacterianas/metabolismo , Prueba de Complementación Genética , Proteínas de Transporte de Membrana/deficiencia , Proteínas de Transporte de Membrana/metabolismo , Mycobacterium tuberculosis/genética , Sinorhizobium meliloti/fisiología , Simbiosis , Antiinfecciosos/farmacología , Proteínas Bacterianas/genética , Medicago sativa/microbiología , Medicago sativa/fisiología , Proteínas de Transporte de Membrana/genética , Sinorhizobium meliloti/efectos de los fármacos , Sinorhizobium meliloti/genética , beta-Defensinas/farmacología
2.
Science ; 256(5055): 377-9, 1992 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-1566085

RESUMEN

Chlamydial cell types are adapted for either extracellular survival or intracellular growth. In the transcriptionally inert elementary bodies, the chromosome is densely compacted; in metabolically active reticulate bodies, the chromatin is loosely organized. Condensation of the chlamydial nucleoid occurs concomitant with expression of proteins homologous to eukaryotic histone H1. When the Chlamydia trachomatis 18-kilodalton histone homolog Hc1 is expressed in Escherichia coli, a condensed nucleoid structure similar to that of chlamydiae is observed with both light and electron microscopy. These results support a role for Hc1 in condensation of the chlamydial nucleoid.


Asunto(s)
Núcleo Celular/ultraestructura , Chlamydia trachomatis/genética , Escherichia coli/ultraestructura , Expresión Génica , Histonas/genética , Western Blotting , Centrifugación por Gradiente de Densidad , Chlamydia trachomatis/ultraestructura , Cromatina/ultraestructura , ADN/metabolismo , Desoxirribonucleasa I , Escherichia coli/genética , Histonas/metabolismo , Histonas/fisiología , Microscopía Inmunoelectrónica
3.
Science ; 272(5268): 1641-3, 1996 Jun 14.
Artículo en Inglés | MEDLINE | ID: mdl-8658136

RESUMEN

Mutations that eliminate KatG catalase-peroxidase activity prevent activation of isoniazid and are a major mechanism of resistance to this principal drug for the treatment of Mycobacterium tuberculosis infections. However, the loss of KatG activity in clinical isolates seemed paradoxical because KatG is considered an important factor for the survival of the organism. Expression of either KatG or the recently identified alkyl hydroperoxidase AhpC was sufficient to protect bacilli against the toxic effects of organic peroxides. To survive during infection, isoniazid-resistant KatG mutants have apparently compensated for the loss of KatG catalase-peroxidase activity by a second mutation, resulting in hyperexpression of AhpC.


Asunto(s)
Antituberculosos/farmacología , Proteínas Bacterianas , Isoniazida/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/genética , Oxidorreductasas/genética , Secuencia de Aminoácidos , Secuencia de Bases , Clonación Molecular , ADN Bacteriano , Farmacorresistencia Microbiana/genética , Sinergismo Farmacológico , Inducción Enzimática , Regulación Bacteriana de la Expresión Génica , Peróxido de Hidrógeno/farmacología , Datos de Secuencia Molecular , Mutación , Mycobacterium bovis/efectos de los fármacos , Mycobacterium bovis/genética , Peroxidasas/biosíntesis , Peroxidasas/genética , Peroxidasas/metabolismo , Peroxirredoxinas , Regiones Promotoras Genéticas
4.
Science ; 280(5369): 1607-10, 1998 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-9616124

RESUMEN

Although isoniazid (isonicotinic acid hydrazide, INH) is widely used for the treatment of tuberculosis, its molecular target has remained elusive. In response to INH treatment, saturated hexacosanoic acid (C26:0) accumulated on a 12-kilodalton acyl carrier protein (AcpM) that normally carried mycolic acid precursors as long as C50. A protein species purified from INH-treated Mycobacterium tuberculosis was shown to consist of a covalent complex of INH, AcpM, and a beta-ketoacyl acyl carrier protein synthase, KasA. Amino acid-altering mutations in the KasA protein were identified in INH-resistant patient isolates that lacked other mutations associated with resistance to this drug.


Asunto(s)
3-Oxoacil-(Proteína Transportadora de Acil) Sintasa/antagonistas & inhibidores , Antituberculosos/farmacología , Isoniazida/farmacología , Mycobacterium tuberculosis/enzimología , 3-Oxoacil-(Proteína Transportadora de Acil) Sintasa/química , 3-Oxoacil-(Proteína Transportadora de Acil) Sintasa/genética , Proteína Transportadora de Acilo/química , Proteína Transportadora de Acilo/genética , Proteína Transportadora de Acilo/metabolismo , Secuencia de Aminoácidos , Farmacorresistencia Microbiana , Inhibidores Enzimáticos/farmacología , Ácidos Grasos/metabolismo , Genes Bacterianos , Humanos , Datos de Secuencia Molecular , Peso Molecular , Mutación , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/genética , Ácidos Micólicos/metabolismo , Tuberculosis/microbiología , Regulación hacia Arriba
5.
Int J Tuberc Lung Dis ; 22(2): 125-132, 2018 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-29506608

RESUMEN

Long-acting/extended-release drug formulations have proved very successful in diverse areas of medicine, including contraception, psychiatry and, most recently, human immunodeficiency virus (HIV) disease. Though challenging, application of this technology to anti-tuberculosis treatment could have substantial impact. The duration of treatment required for all forms of tuberculosis (TB) put existing regimens at risk of failure because of early discontinuations and treatment loss to follow-up. Long-acting injections, for example, administered every month, could improve patient adherence and treatment outcomes. We review the state of the science for potential long-acting formulations of existing tuberculosis drugs, and propose a target product profile for new formulations to treat latent tuberculous infection (LTBI). The physicochemical properties of some anti-tuberculosis drugs make them unsuitable for long-acting formulation, but there are promising candidates that have been identified through modeling and simulation, as well as other novel agents and formulations in preclinical testing. An efficacious long-acting treatment for LTBI, particularly for those co-infected with HIV, and if coupled with a biomarker to target those at highest risk for disease progression, would be an important tool to accelerate progress towards TB elimination.


Asunto(s)
Antituberculosos/uso terapéutico , Preparaciones de Acción Retardada , Tuberculosis Latente/tratamiento farmacológico , Antituberculosos/química , Humanos
6.
Mucosal Immunol ; 11(2): 462-473, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-28745326

RESUMEN

Protection against Mycobacterium tuberculosis (Mtb) infection requires CD4 T cells to migrate into the lung and interact with infected macrophages. In mice, less-differentiated CXCR3+ CD4 T cells migrate into the lung and suppress growth of Mtb, whereas CX3CR1+ terminally differentiated Th1 cells accumulate in the blood vasculature and do not control pulmonary infection. Here we examine CD4 T-cell differentiation and lung homing during primary Mtb infection of rhesus macaques. Mtb-specific CD4 T cells simultaneously appeared in the airways and blood ∼21-28 days post exposure, indicating that recently primed effectors are quickly recruited into the lungs after entering circulation. Mtb-specific CD4 T cells in granulomas display a tissue-parenchymal CXCR3+CX3CR1-PD-1hiCTLA-4+ phenotype. However, most granuloma CD4 T cells are found within the outer lymphocyte cuff and few localize to the myeloid cell core containing the bacilli. Using the intravascular stain approach, we find essentially all Mtb-specific CD4 T cells in granulomas have extravasated across the vascular endothelium into the parenchyma. Therefore, it is unlikely to be that lung-homing defects introduced by terminal differentiation limit the migration of CD4 T cells into granulomas following primary Mtb infection of macaques. However, intralesional positioning defects within the granuloma may pose a major barrier to T-cell-mediated immunity during tuberculosis.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Granuloma del Sistema Respiratorio/inmunología , Pulmón/inmunología , Macaca mulatta/inmunología , Macrófagos Alveolares/inmunología , Mycobacterium tuberculosis/fisiología , Tuberculosis/inmunología , Animales , Antígenos Bacterianos/inmunología , Comunicación Celular , Movimiento Celular , Células Cultivadas , Humanos , Evasión Inmune , Inmunidad Celular , Pulmón/microbiología , Macaca mulatta/microbiología , Ratones , Ratones Endogámicos C57BL , Receptores CXCR3/metabolismo
8.
Int J Tuberc Lung Dis ; 21(10): 1145-1149, 2017 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-28911359

RESUMEN

BACKGROUND: Interferon-gamma (IFN-γ) release assays (IGRAs) are used to diagnose tuberculosis (TB) but not to measure treatment response. OBJECTIVE: To measure IFN-γ response to active anti-tuberculosis treatment. DESIGN: Patients from the Henan Provincial Chest Hospital, Henan, China, with TB symptoms and/or signs were enrolled into this prospective, observational cohort study and followed for 6 months of treatment, with blood and sputum samples collected at 0, 2, 4, 6, 8, 16 and 24 weeks. The QuantiFERON® TB-Gold assay was run on collected blood samples. Participants received a follow-up telephone call at 24 months to determine relapse status. RESULTS: Of the 152 TB patients enrolled, 135 were eligible for this analysis: 118 pulmonary (PTB) and 17 extra-pulmonary TB (EPTB) patients. IFN-γ levels declined significantly over time among all patients (P = 0.002), with this decline driven by PTB patients (P = 0.001), largely during the initial 8 weeks of treatment (P = 0.019). IFN-γ levels did not change among EPTB patients over time or against baseline culture or drug resistance status. CONCLUSION: After 6 months of effective anti-tuberculosis treatment, IFN-γ levels decreased significantly in PTB patients, largely over the initial 8 weeks of treatment. IFN-γ concentrations may offer some value for monitoring anti-tuberculosis treatment response among PTB patients.


Asunto(s)
Antituberculosos/uso terapéutico , Ensayos de Liberación de Interferón gamma/métodos , Tuberculosis Pulmonar/tratamiento farmacológico , Tuberculosis/tratamiento farmacológico , Adulto , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Interferón gamma/sangre , Masculino , Estudios Prospectivos , Factores de Tiempo , Resultado del Tratamiento , Tuberculosis/diagnóstico , Tuberculosis Pulmonar/diagnóstico
9.
Curr Opin Microbiol ; 4(1): 28-34, 2001 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-11173030

RESUMEN

Since the publication of the complete genome sequence of Mycobacterium tuberculosis in 1998, there has been a marked intensification and diversification of activities in the field of tuberculosis research. Among the areas that have advanced spectacularly are comparative genomics, functional genomics-notably the study of the transcriptome and proteome - and cell envelope biogenesis, especially as it relates to the mechanism of action of antimycobacterial drugs.


Asunto(s)
Genes Bacterianos , Genoma Bacteriano , Mycobacterium tuberculosis/genética , Tuberculosis/microbiología , Variación Antigénica , Humanos , Mycobacterium tuberculosis/metabolismo , Mycobacterium tuberculosis/patogenicidad , Proteoma , Transcripción Genética , Tuberculosis/metabolismo , Tuberculosis/patología
10.
Int J Tuberc Lung Dis ; 20(7): 948-54, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27287649

RESUMEN

SETTING: Tuberculosis (TB) remains one of the main concerns in global health. One of the main threats to treatment success is patient non-adherence to anti-tuberculosis treatment. OBJECTIVE: To identify the relation between social conditions and treatment adherence in a prospective cohort setting in an intermediate TB burden country. DESIGN: To identify associations between poor adherence and social conditions, including educational level, type of residence and occupation, we constructed hierarchical logistic regression models. RESULTS: A total of 551 participants were included in the study. Low educational levels, poor housing and occupations in the construction and manufacturing industries and service sectors were associated with poor adherence; this association was likely to be differentiated by previous history of anti-tuberculosis treatment. CONCLUSION: Policy making should focus on improving the social conditions of patients by working towards better housing conditions and providing health promoting working conditions to enable treatment adherence.


Asunto(s)
Antituberculosos/uso terapéutico , Cumplimiento de la Medicación , Condiciones Sociales , Tuberculosis Pulmonar/tratamiento farmacológico , Adulto , Anciano , Distribución de Chi-Cuadrado , Escolaridad , Empleo , Femenino , Promoción de la Salud , Vivienda , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Estudios Prospectivos , República de Corea , Factores de Riesgo , Resultado del Tratamiento , Tuberculosis Pulmonar/diagnóstico , Tuberculosis Pulmonar/psicología , Adulto Joven
11.
Trends Microbiol ; 9(5): 237-41, 2001 May.
Artículo en Inglés | MEDLINE | ID: mdl-11336841

RESUMEN

The complex structure of the cell wall of Mycobacterium tuberculosis clearly contributes to the outcome of the dialogue between this pathogen and its host. The effects of mutations in cell wall components are likely to be quite complex, as individual components of the wall could have indirect effects that extend well beyond the physical integrity of the wall itself. Affected processes include the surface exposure or secretion of the many lipid, glycolipid and proteinaceous molecules that can interact directly with components of the host cell.


Asunto(s)
Pared Celular/fisiología , Mycobacterium tuberculosis/patogenicidad , Pared Celular/química , Pared Celular/genética , Mutación , Mycobacterium tuberculosis/genética , Virulencia/genética
12.
Trends Microbiol ; 4(7): 275-81, 1996 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-8829336

RESUMEN

The intrinsic resistance of many mycobacterial species to chemotherapy is largely attributable to their impermeable cell wall. The composition of the cell wall of a particular species appears to be influenced by the environmental niche that the species occupies. The complex regulatory and biosynthetic pathways involved in cell wall biosynthesis and construction offer useful chemotherapeutic targets against mycobacteria.


Asunto(s)
Pared Celular/química , Mycobacterium/fisiología , Adaptación Fisiológica , Pared Celular/efectos de los fármacos , Pared Celular/fisiología , Etambutol/farmacología , Isoniazida/farmacología , Membrana Dobles de Lípidos/química , Lipopolisacáridos/metabolismo , Modelos Biológicos , Mycobacterium/efectos de los fármacos , Mycobacterium/ultraestructura , Permeabilidad , Fosfatidilinositoles/fisiología
13.
Gene ; 132(1): 137-41, 1993 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-8406036

RESUMEN

Chlamydia trachomatis elementary bodies contain two developmentally expressed histone H1 homologues. An 18-kDa histone homologue, Hc1, is conserved among C. trachomatis serovars and C. psittaci. The other histone homologue, Hc2 (encoded by hctB), varies in size between C. trachomatis serovars but is present in reduced amounts or absent from C. psittaci. The variation in Hc2 size among C. trachomatis serovars was found to be due to internal deletions from a region of the hctB gene encoding lysine- and alanine-rich pentameric repeats.


Asunto(s)
Proteínas Bacterianas , Chlamydia trachomatis/metabolismo , Proteínas de Unión al ADN/genética , Variación Genética , Histonas/genética , Secuencia de Aminoácidos , Chlamydophila psittaci/metabolismo , Clonación Molecular , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Análisis de Secuencia de ADN , Homología de Secuencia de Aminoácido
14.
Microbes Infect ; 2(6): 659-69, 2000 May.
Artículo en Inglés | MEDLINE | ID: mdl-10884617

RESUMEN

Although the primary targets of activated isoniazid (INH) are proteins involved in the biosynthesis of cell wall mycolic acids, clinical resistance is dominated by specific point mutations in katG. Mutations associated with target mutations contribute to, but still cannot completely explain, resistance to INH. Despite the wealth of genetic information currently available, the molecular mechanism of cell death induced by INH remains elusive.


Asunto(s)
Antituberculosos/farmacología , Proteínas Bacterianas , Isoniazida/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/genética , Antituberculosos/química , Farmacorresistencia Microbiana/genética , Humanos , Isoniazida/química , Mutación , Mycobacterium tuberculosis/enzimología , Peroxidasas/genética , Peroxidasas/metabolismo , Tuberculosis Pulmonar/microbiología
15.
Tuberculosis (Edinb) ; 82(4-5): 149-60, 2002.
Artículo en Inglés | MEDLINE | ID: mdl-12464486

RESUMEN

Mycobacterium tuberculosis has two discrete beta-ketoacyl synthases encoded by kasA and kasB that are located in tandem within a five-gene operon that has been implicated in isoniazid-sensitivity and mycolic acid synthesis. We have developed an in vitro meromycolic acid synthase assay to elucidate the anabolic role of these enzymes. Overproduction of KasA and KasB individually and together in M. smegmatis enabled cell-free incorporation of [(14)C]malonyl-CoA into lipids whose chain length was dependent upon the M. tuberculosis elongating enzyme used. KasA specifically elongated palmitoyl-CoA to monounsaturated fatty acids that averaged 40 carbons in length. KasB hyperproduction in the presence of KasA produced longer chain multiunsaturated hydrocarbons averaging 54 carbons in length. These products comigrated with a synthetic standard of meromycolic acid and their production was sensitive to isoniazid, thiolactomycin, and triclosan. KasA mutations associated with isoniazid resistance produced an enzyme that had a diminished overall catalytic activity but conferred enhanced resistance to isoniazid. In vivo analysis confirmed that overexpression of each of the four mutant KasAs enhanced isoniazid resistance when compared to overexpression of wild-type KasA. These results suggest discrete anabolic roles for both KasA and KasB in mycolic acid synthesis and substantiate the involvement of KasA mutations in isoniazid resistance.


Asunto(s)
3-Oxoacil-(Proteína Transportadora de Acil) Sintasa/fisiología , Isoniazida/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Ácidos Micólicos/metabolismo , 3-Oxoacil-(Proteína Transportadora de Acil) Sintasa/genética , Antibióticos Antituberculosos/farmacología , Sistema Libre de Células , Medios de Cultivo , Farmacorresistencia Bacteriana , Ácido Graso Sintasas/antagonistas & inhibidores , Mutación , Mycobacterium smegmatis/efectos de los fármacos , Mycobacterium smegmatis/enzimología , Mycobacterium tuberculosis/enzimología , Mycobacterium tuberculosis/metabolismo , Especificidad por Sustrato , Tiofenos/farmacología , Triclosán/farmacología
16.
Biochem Pharmacol ; 54(11): 1165-72, 1997 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-9416967

RESUMEN

The development of new chemotherapy for the treatment of tuberculosis has three major objectives: first, the development of faster-acting drugs to shorten the duration of treatment; second, the development of novel antimicrobials to counter the emergence of bacteria resistant to current therapies; and, third, the development of chemotherapeutics that specifically target dormant bacilli to treat the one-third of the world's population latently infected with tubercle bacilli. Strategies based upon optimizing the inhibition of known targets require an extensive knowledge of the detailed mechanism of action of current antimycobacterial agents. For many agents such as isoniazid, ethambutol, rifampin, and pyrazinamide such knowledge is now available. Strategies based upon the identification of novel targets will necessitate the identification of biochemical pathways specific to mycobacteria and related organisms. Many unique metabolic processes occur during the biosynthesis of mycobacterial cell wall components, and some attractive new targets have emerged. The development of targets specific to latency will require a detailed picture of the metabolism and biochemical pathways occurring in dormant bacilli. Recent evidence suggests that anaerobic metabolic pathways may operate in dormant bacilli, and the enzymes involved in such pathways may also provide significant new targets for intervention. The combination of the mycobacterial genome sequence that is anticipated to become available this year with an improved understanding of the unique metabolic processes that define mycobacteria as a genus offers the greatest hope for the elimination of one of mankind's oldest enemies.


Asunto(s)
Tuberculosis/tratamiento farmacológico , Animales , Diseño de Fármacos , Farmacorresistencia Microbiana , Etambutol/uso terapéutico , Humanos , Isoniazida/uso terapéutico , Ácidos Micólicos/metabolismo , Pirazinamida/uso terapéutico , Rifampin/uso terapéutico
17.
Biochem Pharmacol ; 59(3): 221-31, 2000 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-10609550

RESUMEN

With the completion of the genome of Mycobacterium tuberculosis comes the promise of a new generation of potent drugs to combat the emerging epidemic of multiply drug-resistant isolates. Translating this genomic information into realistic assays, valid targets, and preclinical drug candidates represents the next great hope in tuberculosis control. We propose a paradigm for exploiting the genome to inform the development of novel antituberculars, utilizing the techniques of differential gene expression as monitored by DNA microarrays coupled with the emerging discipline of combinatorial chemistry. A comparison of currently used antituberculars with the properties of other pharmaceuticals suggests that such compounds will have a defined range of physiochemical properties. In general, we can expect the next generation of antituberculars to be small, relatively hydrophilic molecules that bind tightly to specific cellular targets. Many current antimycobacterials require some form of cellular activation (e.g. the activation of isoniazid by a catalase-peroxidase). Activation corresponds to the oxidative, reductive, or hydrolytic unmasking of reactive groups, which occurs with many current antimycobacterial prodrugs. Understanding the mechanisms involved in activation of current antimycobacterial therapeutics also may facilitate the development of alternative activation strategies or of analogs that require no such processes.


Asunto(s)
Antituberculosos/farmacología , Técnicas Químicas Combinatorias , Diseño de Fármacos , Genoma Bacteriano , Mycobacterium tuberculosis/efectos de los fármacos , Animales , Antituberculosos/química , Antituberculosos/metabolismo , Antituberculosos/uso terapéutico , Biotransformación , Farmacorresistencia Microbiana , Humanos , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/química , Mycobacterium tuberculosis/genética , Profármacos/metabolismo , Relación Estructura-Actividad , Tuberculosis/tratamiento farmacológico
18.
Curr Opin Investig Drugs ; 2(2): 198-201, 2001 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-11816829

RESUMEN

Like many neglected diseases of the developing world, tuberculosis (TB) has a thin portfolio of new compounds currently in the discovery pipeline with near-term clinical potential. Co-development of broad-spectrum antibacterials for TB indications is superficially attractive but unlikely to result in significant advances in therapy. Genomic information has been useful in the redesign of second-line antituberculars such as ethambutol and such molecules will likely soon enter preclinical development. New targets and lead compounds with activity against the mycobacterial cell wall and non-replicating bacilli are the subject of current discovery programs.


Asunto(s)
Antituberculosos/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Anaerobiosis , Humanos , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/metabolismo
19.
FEMS Microbiol Lett ; 207(1): 81-6, 2002 Jan 22.
Artículo en Inglés | MEDLINE | ID: mdl-11886755

RESUMEN

Mycobacterium tuberculosis is an intracellular pathogen which can survive and multiply within the phagosomal compartment of the macrophage, and in doing so has to withstand the various macrophage defense mechanisms, which include limitation of iron and other metals. Analysis of the complete genome sequence of M. tuberculosis revealed an extensive array of cation transporters, including mntH, an orthologue of the eukaryotic Nramp (natural resistance-associated macrophage protein) gene, that encodes a proton-dependent divalent metal transporter. To assess the effect of this transporter on intracellular survival and pathogenesis, an mntH knock-out mutant of M. tuberculosis H37Rv was created and assayed in bone marrow-derived macrophages and in a murine model of tuberculosis. In neither of these systems was any loss of fitness associated with inactivation of mntH, demonstrating that Nramp orthologues are not important determinants of mycobacterial virulence.


Asunto(s)
Proteínas Bacterianas , Proteínas Portadoras/genética , Modelos Animales de Enfermedad , Macrófagos/microbiología , Mycobacterium tuberculosis/patogenicidad , Tuberculosis/microbiología , Animales , Médula Ósea , Proteínas Portadoras/metabolismo , Proteínas de Transporte de Catión/genética , Proteínas de Transporte de Catión/metabolismo , Eliminación de Gen , Humanos , Ratones , Ratones Endogámicos C57BL , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/crecimiento & desarrollo , Tuberculosis/fisiopatología , Virulencia
20.
Methods Mol Med ; 54: 229-45, 2001.
Artículo en Inglés | MEDLINE | ID: mdl-21341079

RESUMEN

Mycobacterial cell wall ultrastructure has been studied through the use of negative staining, electron microscopy (1,2), freeze fracture (3), X-ray diffraction (4), differential scanning calorimetry (5,6), and electron spin resonance spectroscopy. Through the use of these techniques, the cellular envelope has been shown to be highly ordered and organized in a tripartite structure (2,3,7,8). Classical freeze-fracture and freeze-etch electron microscopy studies have established that fragmentation takes place along extended lipid-rich nonaqueous domains. Applied to mycobacteria, these techniques have revealed two fracture sites, an inner cleavage plane within the plasmalamellar membrane and an outer cleavage plane between the mycolic acids and the tenuous outer leaflet (1). These two cleavage sites represent the two domains containing the majority of the lipid material of the bacillus.

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