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Membrane Disruption and Enhanced Inhibition of Cell‐Wall Biosynthesis: A Synergistic Approach to Tackle Vancomycin‐Resistant Bacteria
Author(s) -
Yarlagadda Venkateswarlu,
Samaddar Sandip,
Paramanandham Krishnamoorthy,
Shome Bibek R.,
Haldar Jayanta
Publication year - 2015
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201507567
Subject(s) - biosynthesis , bacteria , vancomycin , chemistry , cell wall , microbiology and biotechnology , biochemistry , biology , enzyme , genetics , staphylococcus aureus
Resistance to glycopeptide antibiotics, the drugs of choice for life‐threatening bacterial infections, is on the rise. In order to counter the threat of glycopeptide‐resistant bacteria, we report development of a new class of semi‐synthetic glycopeptide antibiotics, which not only target the bacterial membrane but also display enhanced inhibition of cell‐wall biosynthesis through increased binding affinity to their target peptides. The combined effect of these two mechanisms resulted in improved in vitro activity of two to three orders of magnitude over vancomycin and no propensity to trigger drug resistance in bacteria. In murine model of kidney infection, the optimized compound was able to bring bacterial burden down by about 6 logs at 12 mg kg −1 with no observed toxicity. The results furnished in this report emphasize the potential of this class of compounds as future antibiotics for drug‐resistant Gram‐positive infections.