New protein pair offers a fresh target against tuberculosis

Tuberculosis remains one of the world's deadliest infectious diseases: in 2023 Mycobacterium tuberculosis (Mtb) caused an estimated 10.8 million cases and 1.25 million deaths. Two of the biggest problems scientists face are the bacterium's ability to enter a dormant state that makes it less vulnerable to drugs and immune attack, and the rise of multi-drug-resistant strains. These challenges make it essential to find new vulnerabilities in the bacterium's biology. One promising target is an enzyme called thiosulfate-sulfurtransferase SseA, a member of the rhodanese-like enzyme family that helps Mtb survive oxidative stress and establish infection inside macrophages. In work led by corresponding author Salvatore Adinolfi, researchers searched for proteins that might regulate SseA and discovered a previously uncharacterized protein encoded by the gene Rv3284. Because of its strong similarity to E. coli SufE, the team named the protein SufE Mtb. The discovery that SufE Mtb interacts with SseA opens a new line of inquiry into how SseA is switched on and how that activation supports Mtb survival under the stressful conditions it encounters in the host.

To understand how SufE Mtb influences SseA, the researchers combined sequence analysis with AI molecular modelling to map how the two proteins fit together. Their work shows a physical interaction in which SufE Mtb binds to the non-catalytic N-terminal domain of SseA. This arrangement appears to position the active sites of both proteins close to each other and to prime a regulatory loop in SseA to undergo an activation-enhancing conformational change. In other words, SufE Mtb acts as an activator or partner for SseA rather than being a passive bystander. The study preserves the exact naming of the components: SseA as the thiosulfate-sulfurtransferase, Rv3284 as the gene encoding SufE Mtb, and highlights that SseA belongs to the rhodanese-like enzyme family that catalyzes sulfur transfer reactions important for Mtb survival. The models provide a mechanistic explanation for why SseA needs a partner to reach full enzymatic activity.

The finding that SseA requires SufE Mtb for efficient activity has several important implications. First, it links the SseA-SufE Mtb interaction directly to the maintenance of redox homeostasis in Mtb, a key factor when the bacterium faces oxidative stress inside immune cells. Second, because SseA activity supports infection of macrophages and helps withstand oxidative challenges, disrupting the interaction with SufE Mtb could weaken Mtb's defenses and make it more vulnerable to existing drugs or the host immune response. The SseA-SufE Mtb complex therefore represents a new and specific molecular target for drug discovery. The research suggests that small molecules or other interventions designed to block binding between SseA and SufE Mtb, or to prevent the conformational change that activates SseA, could be promising strategies. Further experimental validation and drug screening will be needed to move from structural models to potential therapies, but the work charts a clear new path for tuberculosis research.