Ebselen inhibits mycobacterial ESX-1 secretion through modification of EccA1

The type VII secretion system ESX-1 (ESAT-6 secretion system 1) is required for virulence in Mycobacterium tuberculosis and M. marinum. Here, we identify the clinical drug candidate ebselen as an inhibitor of ESX-1 secretion in both organisms. We find that ebselen inhibits the activity of the ESX-1 AAA+ ATPase EccA1, which is required for full ESX-1 secretion and virulence. EccA1 ATPase activity is inhibited through covalent modification of an N-terminal cysteine residue that is outside its ATPase domain. Our findings suggest the potential of ebselen as an anti-virulence drug complement to standard antituberculous therapy regimens, particularly for drug resistant infection. Our findings also provide new insight into the function of the EccA1 protein domains in its ATPase activity and ESX-1 secretion.