Despite tuberculosis (TB) mortality has fallen 47% since 1990, TB remains one of the world's deadliest diseases, resulting in 1.5 million deaths each year. Tuberculous meningitis (TBM) is the most severe manifestation of TB, associated with a high frequency of neurologic sequelae and mortality in more than 30% of adult patients. TBM treatment consists of the same first-line TB drugs as for pulmonary TB: a combination of isoniazid, rifampicin, pyrazinamide and ethambutol for the first 2 months, followed by an additional 4 months of rifampicin and isoniazid, drugs for which several resistant strains are arising. Moreover, to reach the mycobacteria in the brain/meninges, anti-TB drugs have to cross the central nervous system barriers, the blood brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSF) and high concentrations of the antibacterial must be retained within the brain throughout treatment duration for effective management of meningitis. Drugs must pass these barriers passively based on their lipophilicity and molecular size. Therefore, the combination of new chemical entities, acting by novel mode of action, with the nose-to-brain pathway, which can be considered a valid route for the transport of medicinal agents avoiding the BBB, can be considered a valid strategy to be developed for fighting TBM. The project proposed here aims at combining new chemical entities, acting by novel mode of action, with nanovectors for the nose-to-brain (N2B) delivery for TBM treatment.
