A Synthetic Dual Drug Sideromycin Induces Gram-Negative Bacteria To Commit Suicide with a Gram-Positive Antibiotic

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.