RESUMO
After infection with Mycobacterium tuberculosis, a minority of individuals will progress to tuberculosis disease (TB). The risk is higher among persons with well-established risk factors and within the first year after infection. Testing and treating individuals at high risk of progression maximizes the benefits of TB preventive therapy; avoiding testing of low-risk persons will limit potential harms. Several treatment options are available; rifamycin-based regimens offer the best efficacy-safety balance. In this review, we present an overview of the diagnosis and treatment of TB infection, and summarize common clinical scenarios.
Assuntos
Rifamicinas , Tuberculose , Humanos , Antituberculosos/uso terapêutico , Antituberculosos/efeitos adversos , Tuberculose/diagnóstico , Tuberculose/tratamento farmacológico , Tuberculose/prevenção & controle , Rifamicinas/uso terapêuticoRESUMO
New antibiotics are urgently needed to counter the emergence of antimicrobial-resistant pathogenic bacteria. A major challenge in antibiotic drug discovery is to turn potent biochemical inhibitors of essential bacterial components into effective antimicrobials. This difficulty is underpinned by a lack of methods to investigate the physicochemical properties needed for candidate antibiotics to permeate the bacterial cell envelope and avoid clearance by the action of bacterial efflux pumps. To address these issues, here we used a target engagement assay to measure the equilibrium and kinetic binding parameters of antibiotics targeting dihydrofolate reductase (DHFR) in live bacteria. We also used this assay to identify novel DHFR ligands having antimicrobial activity. We validated this approach using the Gram-negative bacteria Escherichia coli and the emerging human pathogen Mycobacterium abscessus. We expect the use of target engagement assays in bacteria to expedite the discovery and progression of novel, cell-permeable antibiotics with on-target activity.
Assuntos
Antibacterianos , Anti-Infecciosos , Antibacterianos/química , Anti-Infecciosos/farmacologia , Escherichia coli/metabolismo , Bactérias Gram-Negativas , Humanos , Tetra-Hidrofolato Desidrogenase/químicaRESUMO
Modern strains of Mycobacterium tuberculosis from the Americas are closely related to those from Europe, supporting the assumption that human tuberculosis was introduced post-contact. This notion, however, is incompatible with archaeological evidence of pre-contact tuberculosis in the New World. Comparative genomics of modern isolates suggests that M. tuberculosis attained its worldwide distribution following human dispersals out of Africa during the Pleistocene epoch, although this has yet to be confirmed with ancient calibration points. Here we present three 1,000-year-old mycobacterial genomes from Peruvian human skeletons, revealing that a member of the M. tuberculosis complex caused human disease before contact. The ancient strains are distinct from known human-adapted forms and are most closely related to those adapted to seals and sea lions. Two independent dating approaches suggest a most recent common ancestor for the M. tuberculosis complex less than 6,000 years ago, which supports a Holocene dispersal of the disease. Our results implicate sea mammals as having played a role in transmitting the disease to humans across the ocean.
Assuntos
Caniformia/microbiologia , Genoma Bacteriano/genética , Mycobacterium tuberculosis/genética , Tuberculose/história , Tuberculose/microbiologia , Zoonoses/história , Zoonoses/microbiologia , Animais , Osso e Ossos/microbiologia , Europa (Continente)/etnologia , Genômica , História Antiga , Migração Humana/história , Humanos , Peru , Filogenia , Tuberculose/transmissão , Zoonoses/transmissãoRESUMO
Population-based studies have used DNA typing of Mycobacterium tuberculosis organisms to estimate the extent of ongoing tuberculosis transmission in various communities and to characterize associated risk factors. The finding of matched DNA "fingerprints" among isolates from an immigrant subgroup may reflect transmission in the adopted country but could also reflect limited diversity among M. tuberculosis organisms within that immigrant community. The authors sought to determine which hypothesis is more likely to explain the high frequency of matched isolates among Haitian-born tuberculosis patients in Montreal, Quebec, Canada. The authors determined the number of different bacterial genotypes in this community as compared with other foreign-born tuberculosis patients and applied a recently described measure of genetic similarity between M. tuberculosis organisms ("genetic distance"). Among 76 Haitian-born tuberculosis patients diagnosed during 1996-1998, the authors identified 47 distinct genotypes on the basis of standard IS6110 DNA typing and categorical analysis. In genetic distance analysis, these 47 genotypes showed as great a genetic diversity as that observed among the 191 distinct genotypes identified in 216 other foreign-born tuberculosis patients. A mycobacterial "founder effect" is unlikely to account for the high proportion of shared isolates among Haitian-born Montrealers. Recent transmission remains the most likely explanation.