RT Journal Article
SR Electronic
T1 Ebselen attenuates mycobacterial virulence through inhibition of ESX-1 secretion
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 828574
DO 10.1101/828574
A1 Morwan M. Osman
A1 Malte L. Pinckert
A1 Sew Peak-Chew
A1 Mark A. Troll
A1 William H. Conrad
A1 Lalita Ramakrishnan
YR 2021
UL http://biorxiv.org/content/early/2021/12/13/828574.abstract
AB The type VII secretion system ESX-1 mediates virulence in Mycobacterium tuberculosis and Mycobacterium marinum. We find that in M. marinum, the synthetic organoselenium compound ebselen inhibits secretion of ESAT-6, a major ESX-1 substrate. We find that ebselen inhibits the in vitro activity of the ESX-1 AAA+ ATPase EccA1, which potentiates ESX-1 substrate secretion and function. Ebselen modifies a cysteine in its N-terminal tetratricopeptide repeat domain that is required for EccA1’s in vitro ATPase activity. Surprisingly, mutational analyses show this this cysteine is not required for ESX-1 secretion or ebselen’s activity, showing that ebselen inhibits ESX-1 secretion independently of inhibiting EccA1 activity in vitro. While the mechanism by which ebselen inhibits ESX-1 secretion remains elusive, we show that it attenuates ESX-1-mediated damage of M. marinum-containing macrophage phagosomes and inhibits intramacrophage growth. Extending our studies to M. tuberculosis, we find that ebselen inhibits ESX-1 secretion and phagosomal membrane damage in this organism. This work provides insight into EccA1 biology. Ebselen is an orally active drug in clinical trials for other conditions and this work suggests its potential in tuberculosis therapy.Competing Interest StatementThe authors have declared no competing interest.