Staphylococcus aureus
susceptibility to complestatin and corbomycin depends on the VraSR two-component system
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ABSTRACT
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.
IMPORTANCE
Although
Staphylococcus aureus
is a common colonizer of the skin and digestive tract of humans and many animals, it is also a versatile pathogen responsible for causing a wide variety and number of infections. Treatment of these infections requires the bacteria to be constantly exposed to antibiotic treatment, which facilitates the selection of antibiotic-resistant strains. The development of new antibiotics is, therefore, urgently needed. In this paper, we investigated the role of the sensory system of
S. aureus
in susceptibility to two new antibiotics: corbomycin and complestatin. The results shed light on the cell-wall synthesis processes that are affected by the presence of the antibiotic and the sensory system responsible for coordinating their activity.
