Most antibiotics kill bacteria directly, but researchers have found a way to attack the tuberculosis bacterium in an entirely different way—by inhibiting a bacterial enzyme that isn’t essential to its existence but is needed for infectivity or survival in the host (Proc. Natl. Acad. Sci. USA, DOI: 10.1073/pnas.0909133107). Targeting a drug to the nonessential enzyme of a pathogen is a strategy drug companies have not generally embraced. But Zhong-Yin Zhang of Indiana University School of Medicine and coworkers show it’s feasible, which could help build momentum for the approach—its advantage being that bugs cannot easily develop resistance to drugs that don’t kill them directly. When Mycobacterium tuberculosis enters the body to cause tuberculosis (TB), macrophage immune cells initiate apoptosis, signaling other immune cells to mount a defense, or they produce cytokines against it. A virulence factor known as mPTPB produced by the bacterium prevents macrophage apoptosis and cytokine production. Zhang and coworkers identified I-A09, an mPTPB inhibitor that reduces mycobacterial survival in infected macrophages, which could lead to a TB treatment or an agent synergistic with other TB drugs.