Selective Cleavage of D-Ala-D-Lac by Small Molecules: Re-Sensitizing Resistant Bacteria to Vancomycin
Gabriela Chiosis,1*
Ivo G. Boneca2
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.
1 Department of Chemistry, Columbia University,
New York, NY 10027, USA.
2 Laboratory of
Microbiology, The Rockefeller University, New York, NY 10021, USA.
*
To whom correspondence should be addressed. E-mail:
chiosisg{at}mskmail.mskcc.org. Inquiries regarding the biological assays should be addressed to I. G. Boneca. E-mail: bonecai{at}pasteur.fr
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.
