Anti-HIV siamycin I directly inhibits autophosphorylation activity of the bacterial FsrC quorum sensor and other ATP-dependent enzyme activities

Abstract

Edited by Richard Cogdell Keywords:Bacterial two-component signal transduction system FsrC Quorum sensing Siamycin I HIV inhibitor Enterococcus faecalis a b s t r a c t Siamycin I disrupts growth and quorum sensing in Enterococcus faecalis. Using purified intact protein, we demonstrate here that quorum membrane sensor kinase FsrC is a direct target of siamycin I, reducing pheromone-stimulated autophosphorylation activity by up to 91%. Inhibition was noncompetitive with ATP as substrate. Other ATP-binding enzymes were also inhibited, including nine other membrane sensor kinases of E. faecalis, Rhodobacter sphaeroides PrrB, porcine Na + -dependent ATPase and the catalytic subunit of bovine protein kinase A, but not bacterial b-galactosidase, confirming targeted inhibition of a wide range of ATP dependent reactions, and elucidating a likely mechanism underlying the lethality of the inhibitor. Structured summary of protein interactions:PrrB phosphorylates PrrB by protein kinase assay (View interaction) FsrC phosphorylates FsrC by protein kinase assay (View interaction) Crown

Hitting the Caspofungin Salvage Pathway of Human-Pathogenic Fungi with the Novel Lasso Peptide Humidimycin (MDN-0010)

“…In a noncompetitive way siamycin I inhibits the autophosphorylation of membrane sensor kinases in Enterococcus faecalis (33). Sensor kinases are members of two-component systems, which were discovered in prokaryotes and later found in some eukaryotes, but not in the animal kingdom.…”

Targeting agr- and agr-Like Quorum Sensing Systems for Development of Common Therapeutics to Treat Multiple Gram-Positive Bacterial Infections

“…Siamycin I, a peptide effective against HIV fusion with human T cells, attenuates the ability of GBAP to activate FsrC and gelatinase production in E. faecalis , but its effects on other LytTR family members has not yet been ascertained [198,199]. Moreover, it is toxic for Enterococcus at doses sufficient for fsr inhibition.…”

Narrow-spectrum inhibitors targeting an alternative menaquinone biosynthetic pathway of Helicobacter pylori

“…The highly constrained lasso structure of this compound (16e21 amino acids in length, with an N-terminal cyclized ring and a C-terminal tail that share a slipknot-like structure) is extremely resistant to thermal, chemical, and proteolytic degradation [41]. Siamycin I has been shown to directly inhibit the autophosphorylation activity of the FsrC quorum sensor of Enterococcus faecalis [42]. Synchrotron radiation circular spectroscopy revealed that the binding of siamycin I to FsrC exerts a significant effect on the local tertiary structures of the TyR and Trp resides of the protein and/or peptide ligands (gelatinase biosynthesis-activating pheromone) and siamycin I [43].…”