Mycobacterium tuberculosis FtsB and PerM interact via a C-terminal helix in FtsB to modulate cell division

Latent infection by Mycobacterium tuberculosis (Mtb) impedes effective tuberculosis therapy and eradication. The protein PerM is essential for chronic Mtb infections in mice and acts via the divisome protein FtsB to modulate cell division. Using transgenic co-expression in Escherichia coli , we studied the Mtb PerM-FtsB interaction in isolation from other Mtb proteins, engineering PerM to enhance expression in the E. coli membrane. We confirmed the reported instability of Mtb FtsB, and we linked FtsB instability to a segment of FtsB predicted to bind cell-division proteins FtsL and FtsQ. Using fluorescence microscopy, we found that PerM stability hinged on its interaction with a C-terminal helix in FtsB. Molecular dynamics results supported the observation that FtsB stabilized PerM, and suggested that interactions at the PerM-FtsB interface differ from our initial structure prediction in a way that is consistent with PerM sequence conservation. Though narrowly conserved, the PerM-FtsB interaction emerges as a potential target for therapy targeting persistent infections by disrupting regulation of cell division. Integrating protein structure prediction, molecular dynamics and single-molecule microscopy, our approach is primed to screen potential inhibitors of the PerM-FtsB interaction and can be straightforwardly adapted to explore other putative interactions.