RESUMEN
Mycobacterial cell walls are complex structures containing a broad range of unusual lipids, glycolipids and other polymers, some of which act as immunomodulators or virulence determinants. Better understanding of the enzymes involved in export processes would enlighten cell wall biogenesis. Bernut et al. () present the findings of a structural and functional investigation of one of the most important transporter families, the MmpL proteins, members of the resistance-nodulation-cell division (RND) superfamily. A Tyr842His missense mutation in the mmpL4a gene was shown to be responsible for the smooth-to-rough morphotype change of the near untreatable opportunistic pathogen Mycobacterium bolletii due to its failure to export a glycopeptidolipid (GPL). This mutation was pleiotropic and markedly increased virulence in infection models. Tyr842 is well conserved in all actinobacterial MmpL proteins suggesting that it is functionally important and this was confirmed by several approaches including replacing the corresponding residue in MmpL3 of Mycobacterium tuberculosis. Structural modelling combined with experimental results showed Tyr842 to be a critical residue for mediating the proton motive force required for GPL export. This mechanistic insight applies to all MmpL proteins and probably to all RND transporters.
Asunto(s)
Proteínas de Transporte de Membrana/metabolismo , Mycobacterium tuberculosis/genética , Pared Celular/metabolismo , Glucolípidos/metabolismo , VirulenciaRESUMEN
Tuberculosis causes nearly two million deaths per year world-wide. In addition multidrug-resistant mycobacterial strains rapidly emerge so novel therapeutic approaches are needed. Recently, several promising mycobacterial target molecules were identified, which are involved in bacterial or host cell signalling e.g. the serine/threonine protein kinases, PknB and PknG, NAD kinase and the NAD synthetase. Here we describe some early efforts in the development of novel signal transduction inhibitory anti-mycobacterial drugs using a multiple target approach, with special emphasis on the kinase inhibitory field. Initially, we are using the Nested Chemical Library (NCL) technology and pharmacophore modelling. A hit-finding library, consisting of approximately 19000 small molecules with a bias for prototypic kinase inhibitors from our NCL library and commercial sources was virtually screened against these validated target molecules. Protein structures for the virtual screening were taken from the published three dimensional crystal structures of the enzymes. The hits from the virtual screening were subsequently tested in enzymatic assay systems. Potent hits were then tested for biological activity in macrophages, infected with mycobacteria. The final goal of this exercise is not only to identify potent anti-mycobacterial substances, but also a common pharmacophore for the mycobacterial target PknG in combination with PknB, NAD kinase and/or NAD synthetase. This common pharmacophore still needs to be a unique pharmacophore for the mycobacterial target proteins over human off-targets. Such a pharmacophore might then drive the optimization of a completely new profile of an antibiotic agent with activity against latent mycobacteria and resistance mycobacterial strains.
Asunto(s)
Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/metabolismo , Transducción de Señal/efectos de los fármacos , Tuberculosis/tratamiento farmacológico , Tuberculosis/metabolismo , Antibacterianos/toxicidad , Evaluación Preclínica de Medicamentos , Farmacorresistencia Bacteriana Múltiple , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Inhibidores Enzimáticos/toxicidad , Humanos , Macrófagos/efectos de los fármacos , Macrófagos/enzimologíaRESUMEN
OBJECTIVE: 'Stockholm syndrome' is a term used to describe the positive bond some kidnap victims develop with their captor. High-profile cases are reported by the media although the diagnosis is not described in any international classification system. Here we review the evidence base on 'Stockholm syndrome'. METHOD: Databases (PubMED, EMBASE, PsycINFO, CINAHL) were systematically searched. We compared features of cases widely reported in the English language media to identify common themes which may form a recognizable syndrome. RESULTS: We identified 12 papers that met inclusion criteria. The existing literature consists mostly of case reports; furthermore there is ambiguity in the use of the term. No validated diagnostic criteria have been described. Four common features were found between the five cases studied. CONCLUSION: There is little published academic research on 'Stockholm syndrome' although study of media reports reveals similarities between well publicized cases. This may be due to reporting and publication bias.