Telavancin inhibits peptidoglycan biosynthesis through preferential targeting of transglycosylation: evidence for a multivalent interaction between telavancin and lipid II
Abstract number: 1732_160
Benton B., Breukink E., Visscher I., Debabov D., Lunde C., Janc J., Mammen M., Humphrey P.
Objectives: Telavancin (TLV) is a novel, rapidly bactericidal lipoglycopeptide with activity against methicillin-resistant Staphylococcus aureus (MRSA). TLV possesses a unique, multivalent, multifunctional mechanism that contributes to enhanced activity and includes inhibition of cell wall peptidoglycan (PG) biosynthesis and disruption of bacterial membrane barrier function. In vitro studies suggest that TLV exhibits superior antibacterial potency relative to vancomycin (VAN); this may be due to the lipophilic decylaminoethyl side chain that targets TLV to the bacterial cell membrane. The objective of this study was to elucidate the mechanistic basis for the enhanced antibacterial action of TLV.
Methods: Isothermal titration calorimetry was used to determine affinities of TLV to 3-lipid II (a water soluble lipid II analogue), and wild-type lipid II embedded in model membrane vesicles made of 1,2-dioleoyl-sn-glycero-3-phosphocholine. PG biosynthesis was evaluated in methicillin-susceptible, methicillin-resistant, and vancomycin-intermediate isolates of S. aureus. Formation of immature (polymerised, non-cross-linked transglycosylation product) or mature (polymerised, cross-linked, the product of transglycosylation then transpeptidation) PG was assayed in intact cells by measuring incorporation of [14C]-GlcNAc into 5% trichloroacetic acid-insoluble material in the presence of penicillin G (immature PG), or into hot 4% sodium dodecylsulphate-insoluble material (mature PG).
Results: The affinity of TLV for the water-soluble lipid II variant was 4.7±0.5×105 M-1; a nearly 35-fold increase in affinity was observed with membrane-bound, wild-type lipid II. Inhibition patterns of immature and mature PG by TLV were distinct from those of VAN. VAN preferentially inhibited the formation of mature PG (transpeptidation reaction product), requiring ~10-fold higher concentration to inhibit transglycosylation. In contrast, TLV appeared to preferentially inhibit the transglycosylation reaction.
Conclusion: TLV inhibits PG polymerisation and cross-linking steps in bacterial cell wall synthesis. The higher affinity of TLV for membrane-bound lipid II (vs the soluble analogue) is consistent with the concept that TLV selectively binds to the bacterial cell membrane. The superior inhibitory potency of TLV toward PG biosynthesis may derive from its membrane-anchoring properties which confer increased binding affinity for the transglycosylase substrate, lipid II.
|Session name:||European Society of Clinical Microbiology and Infectious Diseases|
|Location:||ICC, Munich, Germany|
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