Iterative Chemical Engineering of Vancomycin Leads to Novel Vancomycin Analogs With a High in Vitro Therapeutic Index

@article{Mishra2018IterativeCE,
  title={Iterative Chemical Engineering of Vancomycin Leads to Novel Vancomycin Analogs With a High in Vitro Therapeutic Index},
  author={Nigam M. Mishra and Izabela Agnieszka Stolarzewicz and David Cannaerts and Joris Schuermans and Rob Lavigne and Yannick Looz and Bart Landuyt and Liliane Schoofs and Dominique Schols and Jan Paeshuyse and Peter T. Hickenbotham and Martha R. J. Clokie and Walter Luyten and Erik V. Van der Eycken and Yves Briers},
  journal={Frontiers in Microbiology},
  year={2018},
  volume={9}
}
Vancomycin is a glycopeptide antibiotic that inhibits transpeptidation during cell wall synthesis by binding to the D-Ala-D-Ala termini of lipid II. For long, it has been used as a last resort antibiotic. However, since the emergence of the first vancomycin-resistant enterococci in 1987, vancomycin resistance has become widespread, especially in hospitals. We have synthesized and evaluated 110 vancomycin analogs modified at the C-terminal carboxyl group of the heptapeptide moiety with R2NHR1NH2… Expand
4 Citations
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References

SHOWING 1-10 OF 37 REFERENCES
Extra Sugar on Vancomycin: New Analogues for Combating Multidrug-Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococci.
TLDR
This work synthesized a series of new vancomycin analogues carrying various sugar moieties on the seventh-amino acid phenyl ring and lipophilic substitutions on vancosamine with extensive structure-activity relationship analysis, which leads to better antibiotic-like properties of enhanced efficacy, optimal pharmacokinetics, and lower toxicity. Expand
Membrane active vancomycin analogues: a strategy to combat bacterial resistance.
TLDR
The development of lipophilic cationic vancomycin analogues possessing excellent antibacterial activity against several drug-resistant strains and opens up a great opportunity for the development of novel antibiotics. Expand
Cell Wall Thickening Is a Common Feature of Vancomycin Resistance in Staphylococcus aureus
TLDR
Thickening of the cell wall is a common phenotype of clinical VRSA strains and may be a phenotypic determinant for vancomycin resistance in S. aureus, according to a study subjected to serial daily passage in drug-free medium. Expand
Insights into Key Interactions between Vancomycin and Bacterial Cell Wall Structures
TLDR
The simulations revealed that the removal or chemical modification of N-methyl-leucine significantly weakens the dipeptide binding to the aglycon structure and provides interesting structural insights into glycopeptide–PG binding interactions. Expand
Evaluation of the antibacterial and antibiofilm activities of novel CRAMP-vancomycin conjugates with diverse linkers.
TLDR
These conjugates show a broad-spectrum activity, which is absent in CRAMP or vancomycin alone, and which is strongly improved compared to an equimolar mixture of CRAMP and vancomYcin, and show a strong inhibitory activity against S. Typhimurium biofilm formation. Expand
Synthesis and study of antibacterial activities of antibacterial glycopeptide antibiotics conjugated with benzoxaboroles.
TLDR
Conjugation of antibiotics with benzoxaborole derivatives provides antibiotics with new and useful properties and overcome resistance of Gram-positive bacteria to vancomycin to Teicoplanin aglycone-benzoxaboroles derivatives. Expand
The vancomycin-nisin(1-12) hybrid restores activity against vancomycin resistant Enterococci.
TLDR
It is shown that a hybrid antibiotic that consists of vancomycin and nisin fragments is significantly more active than the separate fragments against vancomYcin resistant entercocci (VRE). Expand
Vancomycin analogues active against vanA-resistant strains inhibit bacterial transglycosylase without binding substrate
TLDR
It is reported that chlorobiphenyl vancomycin analogues that are incapable of binding substrates nevertheless inhibit E. coli PBP1b, which shows that these compounds interact directly with the enzyme, which supports the hypothesis that chlorine derivatives overcome vanA resistance by targeting bacterial transglycosylases. Expand
Analysis of peptidoglycan precursors in vancomycin-resistant Enterococcus gallinarum BM4174.
TLDR
It is demonstrated here that the resistance mechanism in the constitutively vancomycin-resistant Enterococcus gallinarum BM4174 involves an altered pathway of peptidoglycan synthesis and hydrolysis of the normal precursors in the vancomYcin-sensitive pathway. Expand
Peripheral modifications of [Ψ[CH2NH]Tpg4]vancomycin with added synergistic mechanisms of action provide durable and potent antibiotics
Significance In a quest for antibiotics that may display durable clinical lifetimes, analogs of the glycopeptide antibiotics, including vancomycin, have been designed that not only directly overcomeExpand
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