Sideromycin Induces Gram-Negative Bacteria To Commit Suicide with a Gram-Positive Antibiotic
Rui Liu, Patricia A. Miller, Sergei B. Vakulenko, Nichole K. Stewart, William C. Boggess, and Marvin J. Miller* 
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame , Indiana 46556 , United States
J. Med. Chem., Article ASAP
DOI: 10.1021/acs.jmedchem.8b00218
Publication Date (Web): March 19, 2018
Copyright © 2018 American Chemical Society
*E-mail: mmiller1@nd.edu. Phone 574 631 7571.
Abstract
Many antibiotics lack activity against Gram-negative bacteria because they cannot permeate the outer membrane or suffer from efflux and, in the case of β-lactams, are degraded by β-lactamases. Herein, we describe the synthesis and studies of a dual drug conjugate (1) of a siderophore linked to a cephalosporin with an attached oxazolidinone. The cephalosporin component of 1 is rapidly hydrolyzed by purified ADC-1 β-lactamase to release the oxazolidinone. Conjugate 1 is active against clinical isolates of Acinetobacter baumannii as well as strains producing large amounts of ADC-1 β-lactamase. Overall, the results are consistent with siderophore-mediated active uptake, inherent activity of the delivered dual drug, and in the presence of β-lactamases, intracellular release of the oxazolidinone upon cleavage of the cephalosporin to allow the freed oxazolidinone to inactivate its target. The ultimate result demonstrates that Gram-positive oxazolidinone antibiotics can be made to be effective against Gram-negative bacteria by β-lactamase triggered release.
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.8b00218.
- 1H NMR, 13C NMR, LC/MS, MS, EIMS of ADC, and charge deconvoluted electrospray mass spectrum of ADC (PDF)
- Molecular formula strings (CSV)
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