Selective Cleavage of D-Ala-D-Lac by Small Molecules: Re-Sensitizing Resistant Bacteria to Vancomycin

Science  24 Aug 2001:
Vol. 293, Issue 5534, pp. 1484-1487
DOI: 10.1126/science.1060324

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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.

  • * To whom correspondence should be addressed. E-mail: chiosisg{at} Inquiries regarding the biological assays should be addressed to I. G. Boneca. E-mail: bonecai{at}

  • Present address: Memorial Sloan-Kettering Cancer Center, Department of Medicine, New York, NY 10021, USA.

  • Present address: Institut Pasteur, Unite de Pathogenie Bacterienne des Muqueuses, 75724 Paris Cedex 15, France.

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