2 research outputs found
Peptidoglycan Cross-Linking Preferences of <i>Staphylococcus aureus</i> Penicillin-Binding Proteins Have Implications for Treating MRSA Infections
Methicillin-resistant <i>Staphylococcus aureus</i> (MRSA)
infections are a global public health problem. MRSA strains have acquired
a non-native penicillin-binding protein called PBP2a that cross-links
peptidoglycan when the native <i>S. aureus</i> PBPs are
inhibited by β-lactams. It has been proposed that the native <i>S. aureus</i> PBPs can use cell wall precursors having different
glycine branch lengths (penta-, tri-, or monoglycine), while PBP2a
can only cross-link peptidoglycan strands bearing a complete pentaglycine
branch. This hypothesis has never been tested because the necessary
substrates have not been available. Here, we compared the ability
of PBP2a and two native <i>S. aureus</i> transpeptidases
to cross-link peptidoglycan strands bearing different glycine branches.
We show that purified PBP2a can cross-link glycan strands bearing
penta- and triglycine, but not monoglycine, and experiments in cells
provide support for these findings. Because PBP2a cannot cross-link
peptidoglycan containing monoglycine, this study implicates the enzyme
(FemA) that extends the monoglycine branch to triglycine on Lipid
II as an ideal target for small molecules that restore sensitivity
of MRSA to β-lactams
The Mechanism of Action of Lysobactin
Lysobactin, also known as katanosin
B, is a potent antibiotic with
in vivo efficacy against Staphylococcus aureus and Streptococcus pneumoniae. It
was previously shown to inhibit peptidoglycan (PG) biosynthesis, but
its molecular mechanism of action has not been established. Using
enzyme inhibition assays, we show that lysobactin forms 1:1 complexes
with Lipid I, Lipid II, and Lipid II<sub>A</sub><sup>WTA</sup>, substrates in the PG and wall teichoic
acid (WTA) biosynthetic pathways. Therefore, lysobactin, like ramoplanin
and teixobactin, recognizes the reducing end of lipid-linked cell
wall precursors. We show that despite its ability to bind precursors
from different pathways, lysobactin’s cellular mechanism of
killing is due exclusively to Lipid II binding, which causes septal
defects and catastrophic cell envelope damage