RESUMEN

Considering the promising previous results on the remarkable activity exhibited by cobalt(III) and manganese(II) thiosemicarbazone compounds as antibacterial agents, the present study aimed to prepare and then evaluate the antibacterial activity of two different types of Cu(II) complexes based on a 2-acetylpyridine-N(4)-methyl-thiosemicarbazone ligand (Hatc-Me), a monomer complex [CuCl(atc-Me)] and a novel dinuclear complex [{Cu(µ-atc-Me)}2µ-SO4]. The compounds were characterized by infrared spectra, ultraviolet visible and CHN elemental analysis. In addition, the crystalline structures of the complexes were determined by single-crystal X-ray diffraction. In both cases, the Schiff base ligand coordinated in a tridentate mode via the pyridine nitrogen, imine nitrogen and sulfur atoms. The two Cu(II) atoms in the dimer are five coordinate, consisting of three NNS-donor atoms from the thiosemicarbazone ligand connected by a sulfate bridge. The Hirshfeld surface and energy framework of the complexes were additionally analyzed to verify the intermolecular interactions. The biological activity of the Cu(II) salts, the free ligand and its Cu(II) complexes was evaluated against six strains of mycobacteria including Mycobacterium tuberculosis. The complexes showed promising results as antibacterial agents for M. avium and M. tuberculosis, which ranged from 6.12 to 12.73 µM. Furthermore, molecular docking analysis was performed and the binding energy of the docked compound [{Cu(µ-atc-Me)}2µ-SO4] with M. tuberculosis and M. avium strains were extremely favorable (-11.11 and - 14.03 kcal/mol, respectively). The in silico results show that the complexes are potential candidates for the development of new antimycobacterial drugs.

Asunto(s)

Antituberculosos/farmacología , Complejos de Coordinación/farmacología , Tiosemicarbazonas/farmacología , Antituberculosos/síntesis química , Antituberculosos/metabolismo , Antituberculosos/farmacocinética , Proteínas Bacterianas/metabolismo , Complejos de Coordinación/síntesis química , Complejos de Coordinación/metabolismo , Complejos de Coordinación/farmacocinética , Cobre/química , Ligandos , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Estructura Molecular , Mycobacterium avium/efectos de los fármacos , Mycobacterium kansasii/efectos de los fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Unión Proteica , Relación Estructura-Actividad , Termodinámica , Tiosemicarbazonas/síntesis química , Tiosemicarbazonas/metabolismo , Tiosemicarbazonas/farmacocinética

RESUMEN

OBJECTIVES: Mycobacterium kansasii (M. kansasii) pulmonary infection can cause disease with clinical and radiological features similar to tuberculosis. Failure to treat M. kansasii infection is usually associated with resistance; to increase the chance of successful treatment it is important to identify the species and know the susceptibility profile. This study aimed to evaluate the antimycobacterial susceptibility profiles of M. kansasii isolates from Brazil. METHODS: Sixty-nine M. kansasii isolates from 69 patients were identified by partial sequencing of the hsp65 gene, and their susceptibility profiles were analysed by minimal inhibitory concentration (MIC) assays. RESULTS: From 69 isolates, 68 showed susceptibility to clarithromycin, amikacin, and moxifloxacin. Most strains showed high rates of resistance to trimethoprim-sulfamethoxazole and ciprofloxacin. Resistance to rifampicin and ethambutol was found in 12% and 25% of isolates, respectively. CONCLUSIONS: Worrying results were found regarding susceptibility to some drugs used as first-line agents in the treatment of diseases caused by M. kansasii.

Asunto(s)

Antibacterianos/farmacología , Farmacorresistencia Bacteriana Múltiple , Infecciones por Mycobacterium no Tuberculosas/microbiología , Mycobacterium kansasii/efectos de los fármacos , Proteínas Bacterianas/genética , Brasil , Chaperonina 60/genética , Humanos , Pruebas de Sensibilidad Microbiana

RESUMEN

To identify clinical and therapeutic features of pulmonary nontuberculous mycobacterial (PNTM) disease, we conducted a retrospective analysis of patients referred to the Brazilian reference center, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil, who received a diagnosis of PNTM during 1993­2011 with at least 1 respiratory culture positive for NTM. Associated conditions included bronchiectasis (21.8%), chronic obstructive pulmonary disease (20.7%), cardiovascular disease (15.5%), AIDS (9.8%), diabetes (9.8%), and hepatitis C (4.6%).Two patients had Hansen disease; 1 had Marfan syndrome. Four mycobacterial species comprised 85.6% of NTM infections: Mycobacterium kansasii, 59 cases (33.9%); M. avium complex, 53 (30.4%); M. abscessus, 23 (13.2%); and M. fortuitum, 14 (8.0%). A total of 42 (24.1%) cases were associated with rapidly growing mycobacteria. In countries with a high prevalence of tuberculosis, PNTM is likely misdiagnosed as tuberculosis, thus showing the need for improved capacity to diagnose mycobacterial disease as well as greater awareness of PNTM disease prevalence.

Asunto(s)

Enfermedades Pulmonares/microbiología , Infecciones por Mycobacterium no Tuberculosas/microbiología , Complejo Mycobacterium avium/aislamiento & purificación , Mycobacterium kansasii/aislamiento & purificación , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/uso terapéutico , Brasil , Femenino , Humanos , Enfermedades Pulmonares/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Complejo Mycobacterium avium/efectos de los fármacos , Mycobacterium kansasii/efectos de los fármacos , Resultado del Tratamiento , Adulto Joven

RESUMEN

It has recently been shown that the anti-mycobacterial pro-drug thiacetazone (TAC) inhibits the conversion of double bonds of mycolic acid precursors into cyclopropyl rings in Mycobacterium bovis var BCG, M. marimum and M. chelonae by affecting the cyclopropyl mycolic acid synthases (CMASs) as judged by the build-up of unsaturated mycolate precursors. In our hands, TAC inhibits mycolic acid biosynthesis in Mycobacterium tuberculosis and M. kansasii with almost negligible accumulation of those precursors. Our observations that 'de novo' biosynthesis of all the mycolic acid families decreased upon TAC treatment prompted us to analyse the role of each one of the Type II Fatty Acid Synthase (FASII) enzymes. Overexpression of the hadABC operon, encoding the essential FASII dehydratase complex, but not of any of the remaining FASII genes acting on the elongation of fatty acyl chains leading to the synthesis of meromycolic acids, resulted in high level of resistance to TAC in M. tuberculosis. Spontaneous M. tuberculosis and M. kansasii TAC-resistant mutants isolated during this work revealed mutations in the hadABC genes strongly supporting our proposal that these enzymes are new players in the resistance to this anti-mycobacterial compound.

Asunto(s)

Antituberculosos/farmacología , Proteínas Bacterianas/genética , Enoil-CoA Hidratasa/genética , Mycobacterium kansasii/enzimología , Mycobacterium tuberculosis/enzimología , Tioacetazona/farmacología , Secuencia de Aminoácidos , Proteínas Bacterianas/química , Proteínas Bacterianas/metabolismo , Enoil-CoA Hidratasa/química , Enoil-CoA Hidratasa/metabolismo , Acido Graso Sintasa Tipo II/genética , Acido Graso Sintasa Tipo II/metabolismo , Datos de Secuencia Molecular , Mutación , Mycobacterium kansasii/química , Mycobacterium kansasii/efectos de los fármacos , Mycobacterium kansasii/genética , Mycobacterium tuberculosis/química , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/genética , Ácidos Micólicos/metabolismo , Operón , Alineación de Secuencia

RESUMEN

The antimycobacterial activity of (-)-cubebin (1), hinokinin (2), and some of their semisynthetic derivatives, namely (-)-O-acetyl-cubebin (3), (-)-O-methyl-cubebin (4), (-)-O-(N,N-dimethylamine-ethyl)-cubebin (5) and (-)-6,6'-dinitrohinokinin (6), was evaluated against Mycobacterium tuberculosis (ATCC 27294), M. kansasii (ATCC 12478), and M. avium (ATCC 15769). The MIC values ranged from 31.25 to 2000 microg/mL. Among the evaluated compounds, 2 displayed a MIC value of 62.5 microg/mL against M. tuberculosis, while 3 and 4 displayed MIC values of 62.5 and 31.25 microg/mL, respectively, against M. avium. All compounds were inactive against M. kansasii. These are promising results concerning the search for biologically active natural products, highlighting that new approaches to the prevention, treatment, and cure of tuberculosis are extremely important.

Asunto(s)

Antibacterianos/farmacología , Lignanos/farmacología , Mycobacterium avium/efectos de los fármacos , Mycobacterium bovis/efectos de los fármacos , Mycobacterium kansasii/efectos de los fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Antibacterianos/síntesis química , Lignanos/síntesis química , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana , Modelos Moleculares

RESUMEN

In this paper, synthesis, characterization and antimycobacterial properties of a new water-soluble complex identified as silver-mandelate are described. Elemental and thermal analyses are consistent with the formula [Ag(C(6)H(5)C(OH)COO)](n). The polymeric structure was determined by single X-ray diffraction and the two-dimensional structure is based on the bis(carboxylate-O,O') dimer [Ag-O, 2.237(3), 2.222(3) Angstrom]. The structure is extended along both the b and c axes through two oxygen atoms of a bidentate alpha-hydroxyl-carboxylate residue [Ag-OH(hydroxyl), 2.477(3) Angstrom; Ag-O(carboxylate), 2.502(3) Angstrom; O-Ag-O, 63.94(9) degrees]. A strong d(10)-d(10) interaction was observed between two silver atoms. The Ag - Ag distance is 2.8307(15) Angstrom. The NMR (13)C spectrum in D(2)O shows that coordination of the ligand to Ag(I) occurs through the carboxylate group in solution. Potentiometric titration shows that only species with a molar metal:ligand ratio of 2:2 are formed in aqueous solution. The mandelate complex and the silver-glycolate, silver-malate and silver-hydrogen-tartarate complexes were tested against three types of mycobacteria, Mycobacterium avium, Mycobacterium tuberculosis and Mycobacterium kansasii, and their minimal inhibitory concentration (MIC) values were determined. The results show that the four complexes are potential candidates for antiseptic or disinfectant drugs for discharged secretions of patients affected with tuberculosis.

Asunto(s)

Antibacterianos/química , Antibacterianos/síntesis química , Hidroxiácidos/química , Hidroxiácidos/síntesis química , Plata/química , Antibacterianos/farmacología , Cristalografía por Rayos X , Hidroxiácidos/farmacología , Espectroscopía de Resonancia Magnética , Estructura Molecular , Mycobacterium avium/efectos de los fármacos , Mycobacterium kansasii/efectos de los fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Potenciometría , Plata/farmacología , Espectrofotometría Infrarroja , Termodinámica

RESUMEN

A duplicated nitrotienyl derivative was obtained as a by-product from the synthesis of a proposed molecular hybrid of a nitrotienyl derivative and isoniazid with an expected dual antimycobacteria mechanism. The structure was shown to be the 5,5'-dinitro-2-(2,3-diaza-4-(2'-tienyl)buta-1,3-dienyl)tiophene by X-ray crystallography. The minimal inhibitory concentration (MIC) determination of this compound proved to be promising against Mycobacterium pathogenic strains such as M. avium and M. kansasii, although it had a high level of mutagenicity, as observed in mutagenic activity tests.

Asunto(s)

Antituberculosos/síntesis química , Antituberculosos/farmacología , Mycobacterium avium/efectos de los fármacos , Mycobacterium kansasii/efectos de los fármacos , Nitrocompuestos/síntesis química , Nitrocompuestos/farmacología , Tiofenos/síntesis química , Tiofenos/farmacología , Antituberculosos/química , Cristalografía por Rayos X , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Nitrocompuestos/química , Relación Estructura-Actividad , Tiofenos/química

RESUMEN

In the present work the antioxidant and antimycobacterial activities were determined for extracts from Tabernaemontana catharinensis. The extracts' global yields were obtained using supercritical CO2 plus cosolvent. The cosolvents ethanol, isopropyl alcohol, methanol, and water and their mixtures were used. The extracts were fractionated and analyzed by thin-layer chromatography and gas chromatography/flame ionization detection. The antimycobacterial activity was measured against Mycobacterium tuberculosis, Mycobacterium avium, and Mycobacterium kansasii. The antioxidant activity was determined by the coupled reaction of beta-carotene and limonene acid. The average global yield was approximately constant (2.4 +/- 0.1%) for the alcoholic cosolvents and significantly larger (15 +/- 1%) for the cosolvent water and its alcoholic mixtures. The content of alkaloids in the extracts was strongly affected by the cosolvent. The antioxidant activity of the extracts ranged from 53% to 95%. The highest antimycobacterial activity was detected in the alkaloidal fraction (minimum inhibitory concentration = 128 microg/mL), while the lowest was verified in the aqueous fraction (minimum inhibitory concentration >512 microg/mL).

Asunto(s)

Antibacterianos/farmacología , Antioxidantes/farmacología , Cromatografía con Fluido Supercrítico , Extractos Vegetales/farmacología , Tabernaemontana/química , Dióxido de Carbono , Ciclohexenos , Limoneno , Mycobacterium avium/efectos de los fármacos , Mycobacterium kansasii/efectos de los fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Solventes , Terpenos/farmacología , beta Caroteno/farmacología

RESUMEN

Mycobacterium kansasii is the second most common cause of non-tuberculosis mycobacterial diseases in Sao Paulo, Brazil. An important component of the management of infections caused by this organism is antibiotic susceptibility testing. The objective of this study was to determine the drug susceptibility profiles and genotypes of clinical isolates of M. kansasii obtained from patients with or without an infection that met the American Thoracic Society's case definition criteria of M. kansasii disease. One hundred and sixty-nine clinical isolates of M. kansasii collected between 1993 and 1998 in Sao Paulo, Brazil, were tested consecutively. The isolates were genotyped by PCR restriction-enzyme pattern analysis (PRA). Most of the M. kansasii strains were susceptible to isoniazid, streptomycin, rifabutin, rifampicin, clarithromycin, ethionamide, amikacin, clofazimine and cycloserine, and resistant to ethambutol, ciprofloxacin and doxycycline. Of 169 isolates, 167 belonged to the type I PRA genotype and one each belonged to type II and III genotypes. There was no correlation between PRA subtype and M. kansasii disease according to the American Thoracic Society case definition. Clinical trials may be needed to better correlate MIC values with treatment outcomes to identify appropriate parameters for drug-resistance testing of M. kansasii.

Asunto(s)

Antibacterianos/farmacología , Infecciones por Mycobacterium no Tuberculosas/microbiología , Mycobacterium kansasii/efectos de los fármacos , Mycobacterium kansasii/genética , Amicacina/farmacología , Brasil , Ciprofloxacina/farmacología , Claritromicina/farmacología , Clofazimina/farmacología , Cicloserina/farmacología , Dermatoglifia del ADN , ADN Bacteriano/genética , Doxiciclina/farmacología , Farmacorresistencia Bacteriana , Etambutol/farmacología , Etionamida/farmacología , Genotipo , Humanos , Isoniazida/farmacología , Pruebas de Sensibilidad Microbiana , Mycobacterium kansasii/clasificación , Mycobacterium kansasii/aislamiento & purificación , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Rifabutina/farmacología , Rifampin/farmacología , Estreptomicina/farmacología

RESUMEN

The presence of nontuberculous mycobacteria (NTM) was investigated in forty soil samples belonging to the four physiographic regions (Eastern, Central, Southern and Western) that constitute La Pampa province. The presence of NTM in 67.5% of these soil samples was determined. The density of mycobacteria ranged 25-4,500 mycobacteria g-1 dry soil (mean = 516 CFU g-1). Significant differences were found in relation to both the investigated regions (p < 0.01) and the soil pH (r = 0.44*) (P = 0.02). The mycobacteria represented less than 0.00001% of the total aerobic bacteria found in the soils. Twenty-seven isolated mycobacteria were classified according to the culture, biochemical, enzymatic characteristics and antibiotic sensitivity. Mycobacterium fortitium was the dominant mycobacterium and was detected in 63% of the positive soils. This species showed ability for living in sandy to sandy loam soils, within a wide pH range (6.5-9.7) and organic matter (4.15-83.63 g kg-1). Two other species were M. phlei (range = 50-4,500 CFU g-1) and M. kansasii (range = 50-500 CFU g-1).

Asunto(s)

Micobacterias no Tuberculosas/aislamiento & purificación , Microbiología del Suelo , Argentina , Resistencia a Medicamentos , Mycobacterium fortuitum/efectos de los fármacos , Mycobacterium fortuitum/aislamiento & purificación , Mycobacterium kansasii/efectos de los fármacos , Mycobacterium kansasii/aislamiento & purificación , Mycobacterium phlei/efectos de los fármacos , Mycobacterium phlei/aislamiento & purificación , Micobacterias no Tuberculosas/clasificación , Micobacterias no Tuberculosas/efectos de los fármacos

RESUMEN

The presence of nontuberculous mycobacteria (NTM) was investigated in forty soil samples belonging to the four physiographic regions (Eastern, Central, Southern and Western) that constitute La Pampa province. The presence of NTM in 67.5 of these soil samples was determined. The density of mycobacteria ranged 25-4,500 mycobacteria g-1 dry soil (mean = 516 CFU g-1). Significant differences were found in relation to both the investigated regions (p < 0.01) and the soil pH (r = 0.44*) (P = 0.02). The mycobacteria represented less than 0.00001 of the total aerobic bacteria found in the soils. Twenty-seven isolated mycobacteria were classified according to the culture, biochemical, enzymatic characteristics and antibiotic sensitivity. Mycobacterium fortitium was the dominant mycobacterium and was detected in 63 of the positive soils. This species showed ability for living in sandy to sandy loam soils, within a wide pH range (6.5-9.7) and organic matter (4.15-83.63 g kg-1). Two other species were M. phlei (range = 50-4,500 CFU g-1) and M. kansasii (range = 50-500 CFU g-1).(AU)

Asunto(s)

RESEARCH SUPPORT, NON-U.S. GOVT , Micobacterias no Tuberculosas/aislamiento & purificación , Microbiología del Suelo , Argentina , Resistencia a Medicamentos , Micobacterias no Tuberculosas/clasificación , Micobacterias no Tuberculosas/efectos de los fármacos , Mycobacterium fortuitum/efectos de los fármacos , Mycobacterium fortuitum/aislamiento & purificación , Mycobacterium kansasii/efectos de los fármacos , Mycobacterium kansasii/aislamiento & purificación , Mycobacterium phlei/efectos de los fármacos , Mycobacterium phlei/aislamiento & purificación

RESUMEN

BACKGROUND: The lysis-centrifugation system (Isolator system) is a technique with excellent results in the recovery of mycobacteria from blood specimens. This system consists mainly of saponin (SAP), polypropylenglycol (PPG), and sodium polianthol sulfonate (SPS). The objective of this work was to determine the effect of SAP, PPG, and SPS on the growth of Mycobacterium avium, M. kansasii, M. tuberculosis, and M. xenopi in fluid culture media MGIT and Septi-Chek AFB. METHODS: Two concentrations each of SAP, PPG, and SPS were prepared, and were added in 0.1 ml amounts (alone, in pairs and in combination) to fluid media MGIT and Septi-Chek AFB. Fluid culture media were then in individually inoculated with two different concentrations (10(3) and 10(5) CFU/ml) of each of the four mycobacterial strains used in this study. Culture media were incubated at 37 degrees C and were checked for growth daily. RESULTS: SAP, PPG, and SPS did not inhibit growth of mycobacteria but growth of these strains was indeed retarded (a lengthier time was required for detection of bacterial growth compared with the positive control). Final concentrations of SAP, PPG, and SPS which retarded mycobacterial growth varied, depending upon species, mycobacterial inoculum size, and fluid culture media used. CONCLUSIONS: Components included in the lysy-centrifugation system (SAP, PPG, and SPS), either alone or in combination retarded growth of M. avium, M. kansasii, M. tuberculosis, and M. xenopi in 10(3) and 10(5) CFU/ml concentrations in fluid culture media MGIT and Septi-Chek AFB. These results suggest that strategies should be adopted to decrease the concentrations of these three components, present in the sediment of the processed blood by the Isolator System, which eventually are going to be added to fluid media MGIT and Septi-Check AFB.

Asunto(s)

Técnicas Bacteriológicas/métodos , Mycobacterium/efectos de los fármacos , Polianetolsulfonato/farmacología , Propilenglicol/farmacología , Saponinas/farmacología , Medios de Cultivo/química , Medios de Cultivo/farmacología , Mycobacterium/crecimiento & desarrollo , Mycobacterium avium/efectos de los fármacos , Mycobacterium avium/crecimiento & desarrollo , Mycobacterium kansasii/efectos de los fármacos , Mycobacterium kansasii/crecimiento & desarrollo , Mycobacterium xenopi/efectos de los fármacos , Mycobacterium xenopi/crecimiento & desarrollo , Micobacterias no Tuberculosas/crecimiento & desarrollo

RESUMEN

La evaluación de la susceptibilidad de micobacterias tiene tres objetivos fundamentales: medir resistencia primaria, resistencia secundaria y ayudar a la toma de mejores decisiones terapéuticas en algunos pacientes. El estudio de resistencia mediante el método convencional está vigente pero adolece de lentitud en la obtención de resultados. Los métodos automatizados Bacte y permiten acortar esta espera a 7 a 10 días. Otros métodos en desarrollo para el estudio de la resistencia a fármacos antiturbeculosos son la epsilometría (E-test), detección mediante fagos, citometría de flujo y análisis genotípico. Se revisa someramente el principio biológico de cada uno y su utilidad clínico epidemiológica

Asunto(s)

Técnicas In Vitro , Pruebas de Sensibilidad Microbiana , Mycobacterium avium/efectos de los fármacos , Mycobacterium kansasii/efectos de los fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Antibióticos Antituberculosos/administración & dosificación , Antibióticos Antituberculosos/farmacología , Antibacterianos/administración & dosificación , Antibacterianos/farmacología , Farmacorresistencia Microbiana , Citometría de Flujo , Pruebas de Sensibilidad Microbiana/tendencias