Staphylococcus aureus susceptibility to complestatin and corbomycin depends on the VraSR two-component system
Fecha
2023Autor
Versión
Acceso abierto / Sarbide irekia
Tipo
Artículo / Artikulua
Versión
Versión publicada / Argitaratu den bertsioa
Identificador del proyecto
Impacto
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10.1128/spectrum.00370-23
Resumen
The overuse of antibiotics in humans and livestock has driven the emergence and spread of antimicrobial resistance and has therefore prompted research
on the discovery of novel antibiotics. Complestatin (Cm) and corbomycin (Cb) are
glycopeptide antibiotics with an unprecedented mechanism of action that is active
even against methicillin-resistant and daptomycin-resistant Staphylococcus aureus. ...
[++]
The overuse of antibiotics in humans and livestock has driven the emergence and spread of antimicrobial resistance and has therefore prompted research
on the discovery of novel antibiotics. Complestatin (Cm) and corbomycin (Cb) are
glycopeptide antibiotics with an unprecedented mechanism of action that is active
even against methicillin-resistant and daptomycin-resistant Staphylococcus aureus. They
bind to peptidoglycan and block the activity of peptidoglycan hydrolases required for
remodeling the cell wall during growth. Bacterial signaling through two-component
transduction systems (TCSs) has been associated with the development of S. aureus
antimicrobial resistance. However, the role of TCSs in S. aureus susceptibility to Cm
and Cb has not been previously addressed. In this study, we determined that, among
all 16 S. aureus TCSs, VraSR is the only one controlling the susceptibility to Cm and
Cb. Deletion of vraSR increased bacterial susceptibility to both antibiotics. Epistasis
analysis with members of the vraSR regulon revealed that deletion of spdC, which
encodes a membrane protein that scaffolds SagB for cleavage of peptidoglycan strands
to achieve physiological length, in the vraSR mutant restored Cm and Cb susceptibility
to wild-type levels. Moreover, deletion of either spdC or sagB in the wild-type strain
increased resistance to both antibiotics. Further analyses revealed a significant rise in
the relative amount of peptidoglycan and its total degree of cross-linkage in ΔspdC and
ΔsagB mutants compared to the wild-type strain, suggesting that these changes in the
cell wall provide resistance to the damaging effect of Cm and Cb. [--]
Materias
Staphylococcus aureus,
Two-component system,
VraSR,
Complestatin,
Corbomycin,
Autolysins
Editor
American Society for Microbiology
Publicado en
Microbiology Spectrum, (2023), 1-16
Departamento
Universidad Pública de Navarra. Departamento de Ciencias de la Salud /
Nafarroako Unibertsitate Publikoa. Osasun Zientziak Saila
Versión del editor
Entidades Financiadoras
This work was financially supported by the Spanish Ministry of Science and Innovation grant PID2020-113494RB-I00 to I.L. (Agencia Española de Investigación/Fondo Europeo de Desarrollo Regional, European Union) and a Canadian Institutes of Health Research grant (FRN-148463; to G.D.W.).
C.G.A. was supported by a predoctoral contract from the Public University of Navarra. Research in the Cava lab was supported by The Swedish Research Council (VR), The Knut and Alice Wallenberg Foundation (KAW), The Laboratory of Molecular Infection Medicine Sweden (MIMS) and The Kempe Foundation.