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1.
Sci Transl Med ; 14(633): eabj3860, 2022 02 23.
Artículo en Inglés | MEDLINE | ID: mdl-35196022

RESUMEN

A search for alternative Mycobacterium abscessus treatments led to our interest in the two-component regulator DosRS, which, in Mycobacterium tuberculosis, is required for the bacterium to establish a state of nonreplicating, drug-tolerant persistence in response to a variety of host stresses. We show here that the genetic disruption of dosRS impairs the adaptation of M. abscessus to hypoxia, resulting in decreased bacterial survival after oxygen depletion, reduced tolerance to a number of antibiotics in vitro and in vivo, and the inhibition of biofilm formation. We determined that three antimalarial drugs or drug candidates, artemisinin, OZ277, and OZ439, can target DosS-mediated hypoxic signaling in M. abscessus and recapitulate the phenotypic effects of genetically disrupting dosS. OZ439 displayed bactericidal activity comparable to standard-of-care antibiotics in chronically infected mice, in addition to potentiating the activity of antibiotics used in combination. The identification of antimalarial drugs as potent inhibitors and adjunct inhibitors of M. abscessus in vivo offers repurposing opportunities that could have an immediate impact in the clinic.


Asunto(s)
Antimaláricos , Infecciones por Mycobacterium no Tuberculosas , Mycobacterium abscessus , Animales , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Antimaláricos/farmacología , Antimaláricos/uso terapéutico , Ratones , Pruebas de Sensibilidad Microbiana , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Infecciones por Mycobacterium no Tuberculosas/microbiología , Mycobacterium abscessus/fisiología
2.
Vet Immunol Immunopathol ; 215: 109884, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31420066

RESUMEN

Many vaccines against childhood diseases are administered early after birth, but vaccine development studies frequently test efficacy in adult rather than in neonatal animal models. In countries with endemic tuberculosis (TB), Bacillus Calmette-Guerin (BCG) is administered as part of the neonatal vaccine regimen because it prevents against the disseminated form of TB in children, although it has variable efficacy against pulmonary TB. Several promising new vaccines against TB are currently being tested in adult animal models. Here we evaluated neonatal piglets as an animal model to test vaccine efficacy. For this purpose, minipigs were vaccinated or not with BCG 48 h after birth and their immune response followed longitudinally until adolescence. We characterized the memory and activation phenotype of T cells, cytokine profile, and monocyte activation in response to BCG stimulation from 4 weeks of age into adolescence- age of 24 weeks. Immunological responses in vaccinated and non-vaccinated animals were further monitored upon infection with a low dose exposure to Mycobacterium tuberculosis strain HN878 via the aerosol route. Comparing the immunological response elicited by BCG vaccination in minipigs vs similar studies in infants, suggest that minipigs have the potential to serve as an effective neonatal animal model for vaccine development.


Asunto(s)
Vacuna BCG/inmunología , Modelos Animales de Enfermedad , Mycobacterium tuberculosis/inmunología , Porcinos Enanos/inmunología , Tuberculosis Pulmonar/inmunología , Animales , Animales Recién Nacidos , Citocinas/metabolismo , Evaluación Preclínica de Medicamentos/métodos , Femenino , Inmunogenicidad Vacunal , Memoria Inmunológica , Inmunofenotipificación , Estudios Longitudinales , Activación de Linfocitos , Masculino , Monocitos/inmunología , Porcinos , Tuberculosis/inmunología , Tuberculosis Pulmonar/prevención & control
3.
Tuberculosis (Edinb) ; 114: 119-122, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30711150

RESUMEN

Spectinamides are a novel series of spectinomycin analogs being developed for the treatment of tuberculosis. Intrapulmonary aerosol (IPA) administration of lead spectinamide 1599 has previously been shown to be more efficacious than subcutaneous (SC) administration at comparable doses. The objective of the current study was to characterize the disposition of 1599 in plasma and lungs in mice in order to provide a potential rationale for the observed efficacy differences. 200 mg/kg of 1599 was administered to healthy BALB/c mice by SC injection or by IPA delivery. Plasma and major organs were collected at specified time points until 8 h after dosing. Drug concentrations were measured by LC-MS/MS and analyzed by noncompartmental pharmacokinetic analysis. 1599 demonstrated rapid absorption into plasma after IPA and SC administration, resulting in very similar plasma exposure for both routes. In contrast, drug exposure in the lungs was 48 times higher following IPA as compared to SC administration, which is highly desirable as the lungs are the main site of infection in pulmonary TB. The higher local exposure in the lungs is likely the basis for the increased efficacy after IPA compared to SC administration. Overall, this study supports the pulmonary route as a potential pathway for the treatment of tuberculosis with 1599.


Asunto(s)
Antituberculosos/farmacocinética , Espectinomicina/análogos & derivados , Tuberculosis/metabolismo , Administración por Inhalación , Animales , Antituberculosos/administración & dosificación , Disponibilidad Biológica , Evaluación Preclínica de Medicamentos/métodos , Femenino , Inyecciones Subcutáneas , Pulmón/metabolismo , Ratones Endogámicos BALB C , Espectinomicina/administración & dosificación , Espectinomicina/farmacocinética , Tuberculosis/tratamiento farmacológico
4.
Antimicrob Agents Chemother ; 60(9): 5198-207, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27297488

RESUMEN

In recent years, whole-cell-based screens for novel small molecule inhibitors active against Mycobacterium tuberculosis in culture followed by the whole-genome sequencing of spontaneous resistant mutants have identified multiple chemical scaffolds thought to kill the bacterium through the inactivation of the mycolic acid transporter, MmpL3. Consistent with the fact that MmpL3 is required for the formation of the mycobacterial outer membrane, we have conclusively shown in this study, using conditionally regulated knockdown mutants, that mmpL3 is required for the replication and viability of M. tuberculosis, both under standard laboratory growth conditions and during the acute and chronic phases of infection in mice. Speaking for the vulnerability of this target, silencing mmpL3 had a rapid bactericidal effect on actively replicating cells in vitro and reduced by 3 to 5 logs in less than 4 weeks the bacterial loads of acutely and chronically infected mouse lungs, respectively. Depletion of MmpL3 further rendered M. tuberculosis hypersusceptible to MmpL3 inhibitors. The exquisite vulnerability of MmpL3 at all stages of the infection establishes this transporter as an attractive new target with the potential to improve and shorten current drug-susceptible and drug-resistant tuberculosis chemotherapies.


Asunto(s)
Antituberculosos/farmacología , Proteínas Bacterianas/genética , Pulmón/efectos de los fármacos , Proteínas de Transporte de Membrana/genética , Mycobacterium tuberculosis/genética , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis Pulmonar/tratamiento farmacológico , Animales , Carga Bacteriana/efectos de los fármacos , Transporte Biológico , Ciprofloxacina/farmacología , Modelos Animales de Enfermedad , Doxiciclina/farmacología , Femenino , Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Isoniazida/farmacología , Pulmón/microbiología , Pulmón/patología , Proteínas de Transporte de Membrana/deficiencia , Ratones , Ratones Endogámicos C57BL , Pruebas de Sensibilidad Microbiana , Viabilidad Microbiana/efectos de los fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/crecimiento & desarrollo , Mycobacterium tuberculosis/metabolismo , Ácidos Micólicos , Rifampin/farmacología , Tuberculosis Resistente a Múltiples Medicamentos/microbiología , Tuberculosis Resistente a Múltiples Medicamentos/patología , Tuberculosis Pulmonar/microbiología , Tuberculosis Pulmonar/patología
5.
J Antimicrob Chemother ; 69(4): 1057-64, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24222613

RESUMEN

OBJECTIVES: Of the non-tuberculous mycobacteria, Mycobacterium abscessus is particularly refractory to antimicrobial therapy and new agents with activity against these pathogens are urgently needed. The screening of candidate antimicrobial agents against M. abscessus requires a relevant and reproducible animal model of chronic infection. Granulocyte-macrophage colony-stimulating factor knockout (GM-CSF KO) mice were used to develop a new animal model of chronic pulmonary M. abscessus infection that can be used for preclinical efficacy testing of antimicrobial drugs. METHODS: GM-CSF KO mice were infected with a clinical isolate of M. abscessus via intrapulmonary aerosol delivery using a microsprayer device. The clinical condition, histology and cfu of M. abscessus-infected GM-CSF KO mice were evaluated over a period of 4 months. Mice were treated with azithromycin (100 mg/kg) by oral gavage and the clinical condition, histology and bacterial burden was determined after 2 weeks of treatment. RESULTS: We show that pulmonary infection of GM-CSF KO mice with M. abscessus results in a chronic pulmonary infection that lends itself to preclinical testing of new antimicrobial drugs against this bacterium. Azithromycin treatment of M. abscessus-infected GM-CSF KO mice resulted in a lower bacterial burden in the lungs and spleen, weight gain and significant improvement in lung pathology. CONCLUSIONS: Intrapulmonary aerosol infection of GM-CSF KO mice with M. abscessus is a useful animal model for studying pathogenesis as well as pre-clinical testing of new compounds against M. abscessus in acute or chronic phases of infection.


Asunto(s)
Antibacterianos/uso terapéutico , Azitromicina/uso terapéutico , Factor Estimulante de Colonias de Granulocitos y Macrófagos/deficiencia , Infecciones por Mycobacterium/tratamiento farmacológico , Mycobacterium/efectos de los fármacos , Neumonía Bacteriana/tratamiento farmacológico , Animales , Carga Bacteriana , Enfermedad Crónica , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos/métodos , Histocitoquímica , Pulmón/microbiología , Pulmón/patología , Ratones , Ratones Noqueados , Infecciones por Mycobacterium/microbiología , Infecciones por Mycobacterium/patología , Neumonía Bacteriana/microbiología , Neumonía Bacteriana/patología , Bazo/microbiología
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