Existing antipsychotics boost TB drugs in new fast cell-and-mouse screening model

Tuberculosis remains a stubborn infectious disease partly because Mycobacterium tuberculosis (Mtb) grows slowly and because it lives inside immune cells, where many drugs struggle to reach it. These realities slow down discovery efforts: testing candidate drugs against intracellular bacteria takes too long and is hard to scale. To address that bottleneck, a team led by Vivek Rao developed a faster, more practical laboratory model that recreates the key features of Mtb infection inside human immune cells. The researchers used human monocyte-derived THP-1 macrophages infected with the fast-growing pathogenic surrogate Mycobacterium marinum (Mmar). This ex vivo infection model reproduces important aspects of Mtb intracellular infection, including macrophage colonization and innate immune activation, while growing quickly enough to support medium-throughput testing. By matching the host-pathogen interactions of real Mtb infection in a more rapid system, the model is designed to let scientists screen and compare how well antibiotics and host-directed strategies control bacteria that live inside macrophages.

Using this platform, the team performed a screen of FDA-approved antipsychotics to find compounds that work inside infected cells. The screen identified the phenothiazines trifluoperazine (TFP) and fluphenazine (FFP) as promising adjuncts to frontline anti-tuberculosis therapy (ATT). When either phenothiazine was combined with standard TB drugs, the combinations enhanced intracellular bacterial clearance more effectively than the previously reported antidepressant sertraline, with significant control of intracellular bacteria seen within 12 hours of treatment in macrophages. The investigators then tested the enhancers in murine models of TB infection and found that TFP and FFP further potentiated bacterial clearance and tissue recovery when given alongside ATT. Together, these results validate the THP1–Mmar infection model as a rapid, robust, and scalable platform for identifying intracellular antimycobacterial agents and host-directed therapeutics.

The study offers two practical advances. First, the THP1–Mmar infection model provides a faster, scalable way to find drugs that can act where Mtb hides—inside macrophages—so researchers can prioritize candidates that show intracellular activity before investing in lengthy Mtb culture work. Second, the finding that the phenothiazines trifluoperazine (TFP) and fluphenazine (FFP) boost the performance of frontline anti-tuberculosis therapy (ATT) in both cell and murine models points to the potential of repurposing existing FDA-approved drugs as adjuncts, and to the value of pairing pathogen-directed and host-directed approaches. By validating this platform and identifying concrete candidate adjuncts, the work aims to accelerate TB drug discovery and development by focusing efforts on treatments that demonstrate rapid intracellular control and measurable improvement in preclinical infection models.