ABSTRACT
The emergence of multidrug-resistant (MDR) Mycobacterium tuberculosis strains threaten the control of tuberculosis. New antitubercular dihydrosphingosine analogs, named UCIs, have been evaluated in preclinical studies but their cellular and molecular mechanisms of action against M. tuberculosis are still unknown. The aim of this study was to evaluate the effect of UCI exposure on gene expression of drug-sensitive H37Rv and MDR CIBIN:UMF:15:99 clones of M. tuberculosis which were isolated, phenotypically, and genetically characterized, cultured to log phase and treated with UCI compounds; followed by total RNA isolation, reverse transcription and hybridization assays on Affymetrix genomic microarrays. Data were validated with RT-qPCR assays. As results, UCI-05 and UCI-14 exposure increased gltA1 expression in drug-sensitive H37Rv clones. Furthermore, UCI-05 increased lprQ expression in MDR CIBIN:UMF:15:99 M. tuberculosis clones while UCI-14 reduced the expression of this gene in drug-sensitive H37Rv clones. In addition, UCI-05 reduced rpsO expression in drug-sensitive H37Rv clones. We found gene expression alterations that suggest these molecules may alter carbon and lipid metabolism as well as interfere in the protein-producing machinery in M. tuberculosis.
ABSTRACT
The characteristics of tuberculosis (TB) patients related to a chain of recent TB transmissions were investigated. Mycobacterium tuberculosis (MTB) isolates (120) were genotyped using the restriction fragment length polymorphism-IS6110 (R), spacer oligotyping (S) and mycobacterial interspersed repetitive units-variable number of tandem repeats (M) methods. The MTB isolates were clustered and the clusters were grouped according to the similarities of their genotypes. Spearman's rank correlation coefficients between the groups of MTB isolates with similar genotypes and those patient characteristics indicating a risk for a pulmonary TB (PTB) chain transmission were ana- lysed. The isolates showing similar genotypes were distributed as follows: SMR (5%), SM (12.5%), SR (1.67%), MR (0%), S (46.67%), M (5%) and R (0%). The remaining 35 cases were orphans. SMR exhibited a significant correlation (p < 0.05) with visits to clinics, municipalities and comorbidities (primarily diabetes mellitus). S correlated with drug consumption and M with comorbidities. SMR is needed to identify a social network in metropolitan areas for PTB transmission and S and M are able to detect risk factors as secondary components of a transmission chain of TB.
Subject(s)
Genotyping Techniques/methods , Mycobacterium tuberculosis/genetics , Tuberculosis, Pulmonary/microbiology , Tuberculosis, Pulmonary/transmission , Adolescent , Adult , Aged , Aged, 80 and over , Cities , Comorbidity , DNA, Bacterial/isolation & purification , Female , Genotype , Humans , Interspersed Repetitive Sequences/genetics , Male , Mexico/epidemiology , Microbial Sensitivity Tests , Middle Aged , Molecular Epidemiology/methods , Mycobacterium tuberculosis/classification , Mycobacterium tuberculosis/isolation & purification , Polymorphism, Restriction Fragment Length/genetics , Risk Factors , Sociological Factors , Statistics, Nonparametric , Tandem Repeat Sequences/genetics , Tuberculosis, Pulmonary/epidemiology , Tuberculosis, Pulmonary/genetics , Urban Population , Young AdultABSTRACT
The characteristics of tuberculosis (TB) patients related to a chain of recent TB transmissions were investigated. Mycobacterium tuberculosis (MTB) isolates (120) were genotyped using the restriction fragment length polymorphism-IS6110 (R), spacer oligotyping (S) and mycobacterial interspersed repetitive units-variable number of tandem repeats (M) methods. The MTB isolates were clustered and the clusters were grouped according to the similarities of their genotypes. Spearman’s rank correlation coefficients between the groups of MTB isolates with similar genotypes and those patient characteristics indicating a risk for a pulmonary TB (PTB) chain transmission were ana- lysed. The isolates showing similar genotypes were distributed as follows: SMR (5%), SM (12.5%), SR (1.67%), MR (0%), S (46.67%), M (5%) and R (0%). The remaining 35 cases were orphans. SMR exhibited a significant correlation (p < 0.05) with visits to clinics, municipalities and comorbidities (primarily diabetes mellitus). S correlated with drug consumption and M with comorbidities. SMR is needed to identify a social network in metropolitan areas for PTB transmission and S and M are able to detect risk factors as secondary components of a transmission chain of TB.
Subject(s)
Adolescent , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Young Adult , Genotyping Techniques/methods , Mycobacterium tuberculosis/genetics , Tuberculosis, Pulmonary/microbiology , Tuberculosis, Pulmonary/transmission , Cities , Comorbidity , DNA, Bacterial/isolation & purification , Genotype , Interspersed Repetitive Sequences/genetics , Microbial Sensitivity Tests , Mexico/epidemiology , Molecular Epidemiology/methods , Mycobacterium tuberculosis/classification , Mycobacterium tuberculosis/isolation & purification , Polymorphism, Restriction Fragment Length/genetics , Risk Factors , Sociological Factors , Statistics, Nonparametric , Tandem Repeat Sequences/genetics , Tuberculosis, Pulmonary/epidemiology , Tuberculosis, Pulmonary/genetics , Urban PopulationABSTRACT
The resistance of 139 Mycobacterium tuberculosis (MTB) isolates from the city of Monterrey, Northeast Mexico, to first and second-line anti-TB drugs was analysed. A total of 73 isolates were susceptible and 66 were resistant to anti-TB drugs. Monoresistance to streptomycin, isoniazid (INH) and ethambutol was observed in 29 cases. Resistance to INH was found in 52 cases and in 29 cases INH resistance was combined with resistance to two or three drugs. A total of 24 isolates were multidrug-resistant (MDR) resistant to at least INH and rifampicin and 11 MDR cases were resistant to five drugs. The proportion of MDR-TB among new TB cases in our target population was 0.72% (1/139 cases). The proportion of MDR-TB among previously treated cases was 25.18% (35/139 cases). The 13 polyresistant and 24 MDR isolates were assayed against the following seven second-line drugs: amikacin (AMK), kanamycin (KAN), capreomycin (CAP), clofazimine (CLF), ethionamide (ETH), ofloxacin (OFL) and cycloserine (CLS). Resistance to CLF, OFL or CLS was not observed. Resistance was detected to ETH (10.80%) and to AMK (2.70%), KAN (2.70%) and CAP (2.70%). One isolate of MDR with primary resistance was also resistant to three second-line drugs. Monterrey has a high prevalence of MDR-TB among previously treated cases and extensively drug-resistant-MTB strains may soon appear.
Subject(s)
Antitubercular Agents/pharmacology , Mycobacterium tuberculosis/drug effects , Tuberculosis, Multidrug-Resistant/microbiology , Tuberculosis, Pulmonary/microbiology , Adolescent , Adult , Female , Geography, Medical , Humans , Male , Mexico/epidemiology , Microbial Sensitivity Tests , Middle Aged , Risk Factors , Socioeconomic Factors , Tuberculosis, Multidrug-Resistant/epidemiology , Tuberculosis, Pulmonary/epidemiology , Young AdultABSTRACT
The resistance of 139 Mycobacterium tuberculosis (MTB) isolates from the city of Monterrey, Northeast Mexico, to first and second-line anti-TB drugs was analysed. A total of 73 isolates were susceptible and 66 were resistant to anti-TB drugs. Monoresistance to streptomycin, isoniazid (INH) and ethambutol was observed in 29 cases. Resistance to INH was found in 52 cases and in 29 cases INH resistance was combined with resistance to two or three drugs. A total of 24 isolates were multidrug-resistant (MDR) resistant to at least INH and rifampicin and 11 MDR cases were resistant to five drugs. The proportion of MDR-TB among new TB cases in our target population was 0.72% (1/139 cases). The proportion of MDR-TB among previously treated cases was 25.18% (35/139 cases). The 13 polyresistant and 24 MDR isolates were assayed against the following seven second-line drugs: amikacin (AMK), kanamycin (KAN), capreomycin (CAP), clofazimine (CLF), ethionamide (ETH), ofloxacin (OFL) and cycloserine (CLS). Resistance to CLF, OFL or CLS was not observed. Resistance was detected to ETH (10.80%) and to AMK (2.70%), KAN (2.70%) and CAP (2.70%). One isolate of MDR with primary resistance was also resistant to three second-line drugs. Monterrey has a high prevalence of MDR-TB among previously treated cases and extensively drug-resistant-MTB strains may soon appear.
Subject(s)
Adolescent , Adult , Female , Humans , Male , Middle Aged , Young Adult , Antitubercular Agents/pharmacology , Mycobacterium tuberculosis/drug effects , Tuberculosis, Multidrug-Resistant/microbiology , Tuberculosis, Pulmonary/microbiology , Geography, Medical , Mexico/epidemiology , Microbial Sensitivity Tests , Risk Factors , Socioeconomic Factors , Tuberculosis, Multidrug-Resistant/epidemiology , Tuberculosis, Pulmonary/epidemiologyABSTRACT
Natural azorellane and mulinane diterpenoids show antituberculosis activity, which is increased by methylation of their free carboxyl group. We have systematically investigated the effect of alkylation in this class of diterpenoids and found that the profile of bioactivity is relatively unaffected by the introduction of short alkyl groups, both linear and branched. In this investigation, three semisynthetic diterpenoids, 13 hydroxy-mulin-11-en-20-oic acid n-propyl ester (3) and the n-propyl (19) and n-butyl (20) esters of isomulinic acid, showed the strongest antituberculosis activity (MIC=6.25 microg/mL) against a drug-resistant strain of Mycobacterium tuberculosis.
Subject(s)
Antitubercular Agents/pharmacology , Apiaceae/chemistry , Diterpenes/pharmacology , Mycobacterium tuberculosis/drug effects , Plant Extracts/pharmacology , Alkylation , Antitubercular Agents/chemical synthesis , Diterpenes/chemical synthesis , Diterpenes/isolation & purification , Diterpenes/metabolism , Drug Resistance , Microbial Sensitivity Tests , Molecular Structure , Plant Extracts/isolation & purification , Plant Extracts/metabolismABSTRACT
BACKGROUND: Tuberculosis is a chronic disease caused mainly by Mycobacterium tuberculosis. The emergence of antibiotic-resistant strains of this species underscores the need for novel effective drugs against resistant mycobacteria as first-line antituberculosis medications. METHODS: Crude aqueous (obtained by decoction, in accordance with the traditional mode of preparation), methanol, acetone, and hexane extracts from aerial parts of Artemisia ludoviciana Nutt., Chenopodium ambrosioides L., Marrubium vulgare L., Mentha spicata L., and Flourensia cernua DC were assessed for their ability to either inhibit the growth of or kill M. tuberculosis strains H37Rv and CIBIN:UMF:15:99, the former being sensitive to, and the latter resistant to, streptomycin, isoniazide, rifampin, ethambutol, and pyrazinamide. These five plant species are used in Mexico to treat respiratory disorders. RESULTS: Flourensia cernua was the uniquely active plant among those evaluated. Its hexane and acetone extracts not only inhibited the growth of but killed M. tuberculosis. The hexane extract showed a minimal inhibitory concentration (MIC) of 50 and 25 microg/mL against sensitive and resistant strains, respectively; the acetone extract was active against only CIBIN:UMF:15:99 (MIC = 100 microg/mL). CONCLUSIONS: The hexane extract from F. cernua leaves could be an important source of bactericidal compounds against multidrug-resistant M. tuberculosis.
Subject(s)
Anti-Bacterial Agents/pharmacology , Asteraceae/chemistry , Drug Resistance, Multiple, Bacterial/drug effects , Mycobacterium tuberculosis/growth & development , Plant Components, Aerial/chemistry , Plant Extracts/pharmacology , Acetone/chemistry , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/therapeutic use , Chronic Disease , Hexanes/chemistry , Microbial Sensitivity Tests , Plant Extracts/chemistry , Plant Extracts/therapeutic use , Tuberculosis, Multidrug-Resistant/drug therapyABSTRACT
La falta de apego al tratamiento, el descuido de la vigilancia epidemiológica y el SIDA son algunos de los factores que han favorecido el incremento de la TB en el mundo y el surgimiento de cepas resistentes a los medicamentos antituberculosos de primera y segunda líneas; lo cual pone en riesgo el éxito de las campañas de control de la TB. En este artículo se revisa la situación actual en el mundo sobre la prevalencia de resistencia a medicamentos de primera línea, los mecanismos de acción de los medicamentos antituber-culosos de primera línea y de adquisición de resistencia de las micobacterias. Las conclusiones de este análisis son las siguientes: La resistencia de M. tuberculosis a los medicamentos antituberculosos es la amplificación hecha por el hombre de un fenómeno natural. La administración del tratamiento acortado estrictamente supervisado (TAES) parece ser la forma más efectiva de disminuir esta resistencia, pero se requiere del esfuerzo concertado de los gobiernos y de la sociedad. Es necesario fomentar y apoyar la investigación básica y epidemiológica de la TB y desarrollar y perfeccionar métodos de diagnóstico más rápidos y confiables, nuevos medicamentos antituberculosos y mejorar la efectividad de las vacunas contra TBP (AU)
The insufficient adherence to anti-tuberculosis treatment, the careless of epidemiological surveillance, and HIV/AIDS raising are some factors that have favored TB prevalence and spread of multidrug resistant M. tuberculosis strains. These facts threat the TB control campaigns. In this article the current state of prevalence of resistance to first-line drugs, the action mechanisms of these medications and resistance mechanisms to these compounds are analyzed. The conclusions of this analysis are the following: The M. tuberculosis resistance to anti-TB medications is an amplification of a natural phenomenon due to man. The administration of direct observed therapy shortened (DOTS) appears to be the most effective way to diminish TB and multidrug resistant M. tuberculosis strains, but the effort of governments and worldwide society is required. Besides, basic and epidemiological research needs to be supported, as well as the search to develop and improve more rapid and reliable diagnostic methods, new anti-TB medications and more effective anti-TB vaccines (AU)
Subject(s)
Humans , Tuberculosis/drug therapy , Antitubercular Agents/pharmacokinetics , Mycobacterium tuberculosis/isolation & purification , Tuberculosis/epidemiology , Drug Resistance, Multiple, Bacterial , Mycobacterium tuberculosis/pathogenicity , Microbial Sensitivity Tests/methods , Protein Synthesis Inhibitors/pharmacokineticsABSTRACT
Entre 1974 y 1981 se tipificaron en México 4 522 cepas de Salmonella. De ellas, 1 619 procedían de alimentos, 100 de aguas de drenaje y animales, y 2 803 eran de origen humano. De los 80 tipos que se identificaron 35 no se habían reconocido con anterioridad. En cuanto a la frecuencia con que se aisló cada serotipo, Salmonella typhimurium ocupó el primer lugar en humanos (45,7%) seguido por S. derby (8,6%) y S. newport (7.8%); en alimentos S. derby fue el más frecuente (27,9%) seguido por S. anatum (9,6%) y S. typhimurium (8,9%). S. typhimurium se aisló con más frecuencia de pacientes de hospitales que de los que asistían a laboratorios clínicos privados (53,0 y 24,1% respectivamente), aunque predominó en ambos casos. Se destaca el aumento de la frecuencia de S. newport a partir de 1979 en las cepas de origen humano provenientes en su mayor parte de dos hospitales de la ciudad de México. Este incremento no se observó, sin embargo, en cepas procedentes de alimentos o de otras fuentes
