Selective cleavage of D-Ala-D-Lac by small molecules: re-sensitizing resistant bacteria to vancomycin.
Pathogenic enterococci are becoming resistant to currently available antibiotics, including vancomycin, the drug of last resort for Gram-positive infections. Enterococci pose a significant public health threat, not least because of the risk of transferring vancomycin resistance to the ubiquitous Staphylococcus aureus. Vancomycin resistance is manifested by cell wall peptidoglycan precursors with altered termini that cannot bind the antibiotic. Small molecules with well-oriented nucleophile-electrophile assembly and complementary chirality to the peptidoglycan termini were identified as catalytic and selective cleavers of the peptidoglycan precursor depsipeptide. These molecules were tested in combination with vancomycin and were found to re-sensitize vancomycin-resistant bacteria to the antibiotic.
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Department of Chemistry, Columbia University, New York, NY 10027, USA. chiosisg@mskmail.mskcc.org
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D000409:Alanine / Q000031:analogs & derivatives / Q000378:metabolism*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002384:Catalysis; D020650:Combinatorial Chemistry Techniques; D003198:Computer Simulation; D015195:Drug Design; D004357:Drug Synergism; D016983:Enterococcus / Q000187:drug effects* / Q000378:metabolism; D013293:Enterococcus faecalis / Q000187:drug effects / Q000378:metabolism; D016984:Enterococcus faecium / Q000187:drug effects / Q000378:metabolism; D006868:Hydrolysis; D007773:Lactates / Q000378:metabolism*; D008782:Methylurea Compounds / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D019151:Peptide Library; D010457:Peptidoglycan / Q000737:chemistry / Q000378:metabolism*; D011498:Protein Precursors / Q000378:metabolism; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D013237:Stereoisomerism; D014640:Vancomycin / Q000378:metabolism / Q000494:pharmacology*; D020713:Vancomycin Resistance
D000900:Anti-Bacterial Agents; D007773:Lactates; D008782:Methylurea Compounds; D009842:Oligopeptides; D019151:Peptide Library; D010457:Peptidoglycan; C434449:ProC5 compound; D011498:Protein Precursors; D011759:Pyrrolidines; C434448:benzyl-lysyl-prolyl-seryl-dimethylurea; C078877:alanyllactate; D014640:Vancomycin; D000409:Alanine