Tuberculosis (TB) is a difficult to treat disease caused by the bacterium Mycobacterium tuberculosis. The need for improved
therapies is required to kill different M.
tuberculosis populations present during
infection and to kill drug resistant strains.
Protein complexes associated with energy generation, required for the survival of all M.
tuberculosis populations, have shown promise as targets for novel
therapies (e.g.,
phenothiazines that target type II
NADH dehydrogenase (NDH-2) in the electron transport chain). However, the low efficacy of these compounds and their off-target effects has made the development of
phenothiazines as a therapeutic agent for TB limited. This study reports that a series of alkyltriphenylphosphonium (alkylTPP)
cations, a known intracellular delivery functionality, improves the localization and effective concentration of
phenothiazines at the mycobacterial membrane. AlkylTPP
cations were shown to accumulate at biological membranes in a range of bacteria and lipophilicity was revealed as an important feature of the structure-function relationship. Incorporation of the alkylTPP cationic function significantly increased the concentration and potency of a series of
phenothiazine derivatives at the mycobacterial membrane (the site of NDH-2), where the lead compound 3a showed inhibition of M.
tuberculosis growth at 0.5μg/mL. Compound 3a was shown to act in a similar manner to that previously published for other active
phenothiazines by targeting energetic processes (i.e.,
NADH oxidation and oxygen consumption), occurring in the mycobacterial membrane. This shows the enormous potential of alkylTPP
cations to improve the delivery and therefore efficacy of bioactive agents targeting oxidative phosphorylation in the mycobacterial membrane.