RESUMO
Nanoenabled drug delivery systems against tuberculosis (TB) are thought to control pathogen replication by targeting antibiotics to infected tissues and phagocytes. However, whether nanoparticle (NP)-based carriers directly interact with Mycobacterium tuberculosis and how such drug delivery systems induce intracellular bacterial killing by macrophages is not defined. In the present study, we demonstrated that a highly hydrophobic citral-derived isoniazid analogue, termed JVA, significantly increases nanoencapsulation and inhibits M. tuberculosis growth by enhancing intracellular drug bioavailability. Importantly, confocal and atomic force microscopy analyses revealed that JVA-NPs associate with both intracellular M. tuberculosis and cell-free bacteria, indicating that NPs directly interact with the bacterium. Taken together, these data reveal a nanotechnology-based strategy that promotes antibiotic targeting into replicating extra- and intracellular mycobacteria, which could actively enhance chemotherapy during active TB.
Assuntos
Antituberculosos/farmacologia , Isoniazida/análogos & derivados , Isoniazida/farmacologia , Macrófagos/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Nanopartículas , Animais , Disponibilidade Biológica , Células Cultivadas , Composição de Medicamentos , Sistemas de Liberação de Medicamentos/métodos , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Ácido Láctico/química , Macrófagos/microbiologia , Camundongos , Microscopia de Força Atômica , Microscopia Confocal , Mycobacterium tuberculosis/fisiologia , Tamanho da Partícula , Fagocitose , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/microbiologiaRESUMO
Hedyosmum brasiliense Miq. is an endemic aromatic arborescent shrub that is the only representative of the Chloranthaceae in Brazil. There have been few studies seeking to determine its chemical constituents and/or pharmacological effects. This work describes the isolation and identification of sesquiterpene lactones from the leaves, including guaianolides, elemanolides and a lindenanolide. These were tested against Mycobacterium tuberculosis, together with podoandin, onoseriolide and some other common phenolics. The structures of the isolated compounds were determined based on extensive analysis of 1D and 2D NMR spectroscopic and MS data, as well as comparison with published data. The compounds found were the guaianolides, 1,2-epoxy-10α-hydroxy-podoandin and 1-hydroxy-10,15-methylenepodoandin, the elemenolide 15-acetoxy-isogermafurenolide and the lindenanolide 8α/ß,9α-hydroxy-onoseriolide, along with the previously isolated guaianolide podoandin, the lindenanolide onoseriolide and the elemenolide 15-hydroxy-isogermafurenolide. The phenolic compounds isolated were scopoletin, vanillin, vanillic acid, protocatechuic aldehyde and ethyl caffeate. The isolated sesquiterpene lactones did not show anti-mycobacterial activity against isoniazid-sensitive M. tuberculosis cultures at concentrations of 1-30 µM.