Genomic studies and experiments with permeability-deficient
strains
have revealed a variety of biological targets that can be engaged
to kill Gram-negative bacteria. However, the formidable outer membrane
and promiscuous efflux pumps of these pathogens prevent many candidate
antibiotics from reaching these targets. One such promising target
is the enzyme FabI, which catalyzes the rate-determining step in bacterial
fatty acid biosynthesis. Notably, FabI inhibitors have advanced to
clinical trials for Staphylococcus aureus infections
but not for infections caused by Gram-negative bacteria. Here, we
synthesize a suite of FabI inhibitors whose structures fit permeation
rules for Gram-negative bacteria and leverage activity against a challenging
panel of Gram-negative clinical isolates as a filter for advancement.
The compound to emerge, called fabimycin, has impressive activity
against >200 clinical isolates of Escherichia coli, Klebsiella pneumoniae, and Acinetobacter
baumannii, and does not kill commensal bacteria. X-ray structures
of fabimycin in complex with FabI provide molecular insights into
the inhibition. Fabimycin demonstrates activity in multiple mouse
models of infection caused by Gram-negative bacteria, including a
challenging urinary tract infection model. Fabimycin has translational
promise, and its discovery provides additional evidence that antibiotics
can be systematically modified to accumulate in Gram-negative bacteria
and kill these problematic pathogens.
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