Po-Chao Wen, Juan M Vanegas, Susan B Rempe, and Emad Tajkhorshid.
Probing key elements of teixobactin-lipid II interactions in
membrane.
Chemical Science, 9:6997-7008, 2018.
(PMC: PMC6124899)
WEN2018A-ET
Teixobactin (Txb) is a recently discovered antibiotic against Gram-positive
bacteria that induces no detectable resistance. The bactericidal mechanism
is believed to be the inhibition of cell wall biosynthesis by Txb binding to lipid
II and lipid III. Txb binding specificity likely arises from targeting of the shared
lipid component, the pyrophosphate moiety. Despite synthesis and
functional assessment of numerous chemical analogs of Txb, and
consequent identification of the Txb pharmacophore, the detailed structural
information of Txb-substrate binding is still lacking. Here, we use molecular
modeling and microsecond-scale molecular dynamics simulations to capture
the formation of Txb-lipid II complexes at a membrane surface. Two
dominant binding conformations were observed, both showing characteristic
lipid II phosphate binding by the Txb backbone amides near the C-terminal
cyclodepsipeptide (D-Thr8–Ile11) ring. Additionally, binding by Txb also
involved the side chain hydroxyl group of Ser7, as well as a secondary
phosphate binding provided by the side chain of L-allo-enduracididine.
Interestingly, those conformations differ by swapping two groups of
hydrogen bond donors that coordinate the two phosphate moieties of lipid II,
resulting in opposite orientations of lipid II binding. In addition, residues D-
allo-Ile5 and Ile6 serve as the membrane anchors in both Txb conformations,
regardless of the detailed phosphate binding interactions near the
cyclodepsipeptide ring. The role of hydrophobic residues in Txb activity is
primarily for its membrane insertion, and subsidiarily to provide non-polar
interactions with lipid II tail. Based on the Txb-lipid II interactions captured in
their complexes, as well as their partitioning depths into the membrane, we
propose that the bactericidal mechanism of Txb is to arrest cell wall
synthesis by selectively inhibiting the transglycosylation of peptidoglycan,
while possibly leaving the transpeptidation step unaffected. The observed
“pyrophosphate caging” mechanism of lipid II inhibition appears to be similar
to some lantibiotics, but different from that of vancomycin or bacitracin.
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