Figure 5. Differential prodrug activation of lansoprazole (LPZ).

The proton-pump inhibitor LPZ is converted to a sulfenic acid intermediate in the acidic environment of the gastric gland lumen outside the parietal cell. Further prodrug activation to a sulfenamide (not shown) allows binding to the gastric H⁺K⁺-ATPase and its inhibition. We were able to show that sulfoxide reduction in the cytoplasm of Mtb-host cells converts LPZ to the potent antituberculous agent LPZS, which is active against MDR-TB. We provide evidence that LPZS targets cytochrome bc₁ (complex III) leading to disruption of the mycobacterial respiratory chain and rapid ATP depletion. Conversion of LPZS to the sulfenic acid intermediate necessary for inactivation of the gastric H⁺K⁺-ATPase is not possible, making LPZS a highly selective lead compound for the tuberculosis drug pipeline.