Mycobactin: From target to tool in development of therapeutics for tuberculosis

Abstract

Siderophores are small organic molecules produced by many species of bacteria to sequester iron, an essential metal, from their environment; Mycobacterium tuberculosis produces siderophores known as mycobactins. Mycobactins have been hypothesized to be important for overcoming nutritional immunity that limits the access of M tuberculosis to iron in a host during infection, potentially mediated by the host iron transporter Nramp. As a result, the biosynthesis of mycobactins may be an attractive drug target. Some mycobactins are also known to have antigenic properties, with the precursor dideoxycarboxymycobactin being presented through the CD 1 a lipid presentation pathway. These antigenic mycobactins may be used in vaccine development to direct the host immune response or as adjuvants. It has also been proposed that mycobactins may be used as a "Trojan Horse" to deliver drugs to bacterial cells with a high degree of specificity. A large barrier to these latter uses is the difficulty of acquiring bulk mycobactin for experimentation and drug development, due to the constraints of working under Biosafety Level 3 conditions and with a slow growing organism. Here we describe data from an aerosol infection model in mice that suggest that mycobactins may not be as critical to overcoming nutritional immunity as previously thought, whether in the presence or absence of functional host Nramp. However, we have also generated attenuated strains of M tuberculosis that accumulate mycobactin at a rapid pace under standard culture conditions, and recombinant strains of the model organism Mycobacterium smegmatis that may produce mycobactins from M tuberculosis. Use of these strains will greatly facilitate the production of mycobactin for immunological assays and therapeutic development.