A novel phosphodiesterase of the GdpP family modulates cyclic di-AMP levels in response to cell membrane stress in daptomycin-resistant enterococci
Cargando...
Fecha
2020
Título de la revista
Publicado en
Antimicrobial Agents and Chemotherapy, 1098-6596, Vol. 61, No. 3, 2017, p. 510-513
Publicado por
American Society for Microbiology
URL de la fuente
ISSN de la revista
Título del volumen
Resumen
Descripción
Abstract
Substitutions in the LiaFSR membrane stress pathway are frequently associated with the emergence of antimicrobial peptide resistance in both Enterococcus faecalis and Enterococcus faecium Cyclic di-AMP (c-di-AMP) is an important signal molecule that affects many aspects of bacterial physiology, including stress responses. We have previously identified a mutation in a gene (designated yybT) in E. faecalis that was associated with the development of daptomycin resistance, resulting in a change at position 440 (yybTI440S) in the predicted protein. Here, we show that intracellular c-di-AMP signaling is present in enterococci, and on the basis of in vitro physicochemical characterization, we show that E. faecalisyybT encodes a cyclic dinucleotide phosphodiesterase of the GdpP family that exhibits specific activity toward c-di-AMP by hydrolyzing it to 5'pApA. The E. faecalis GdpPI440S substitution reduces c-di-AMP phosphodiesterase activity more than 11-fold, leading to further increases in c-di-AMP levels. Additionally, deletions of liaR (encoding the response regulator of the LiaFSR system) that lead to daptomycin hypersusceptibility in both E. faecalis and E. faecium also resulted in increased c-di-AMP levels, suggesting that changes in the LiaFSR stress response pathway are linked to broader physiological changes. Taken together, our data show that modulation of c-di-AMP pools is strongly associated with antibiotic-induced cell membrane stress responses via changes in GdpP activity or signaling through the LiaFSR system.
Palabras clave
Keywords
Enterococcus faecalis, Enterococcus faecium, GdpP, LiaFSR, C-di-AMP, Cyclic dinucleotide, Daptomycin, Enterococci, Membrane stress