Novel FR-900493 Analogues That Inhibit the Outgrowth of Clostridium difficile Spores
The spectrum of antibacterial activity for the nucleoside antibiotic FR-900493 (1) can be extended by chemical modifications. We have generated a small focused library based on the structure of 1 and identified UT-17415 (9), UT-17455 (10), UT-17460 (11), and UT-17465 (12), which exhibit anti-Clostridium difficile growth inhibitory activity. These analogues also inhibit the outgrowth of C. difficile spores at 2× minimum inhibitory concentration. One of these analogues, 11, relative to 1 exhibits over 180-fold and 15-fold greater activity against the enzymes, phospho-MurNAc-pentapeptide translocase (MraY) and polyprenyl phosphate-GlcNAc-1-phosphate transferase (WecA), respectively. The phosphotransferase inhibitor 11 displays antimicrobial activity against several tested bacteria including Bacillus subtilis, Clostridium spp., and Mycobacterium smegmatis, but no growth inhibitory activity is observed against the other Gram-positive and Gram-negative bacteria. The selectivity index (Vero cell cytotoxicity/C. difficileantimicrobial activity) of 11 is approximately 17, and 11 does not induce hemolysis even at a 100 μM concentration.
© 2018 American Chemical Society. This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. Received 7 November 2017. Date accepted 26 January 2018. Published online 9 February 2018. Published in print 28 February 2018. The National Institutes of Health is gratefully acknowledged for financial support of this work (grant GM114611). M.K. thanks the University of Tennessee Health Science Center for generous financial support (CORNET award). NMR data were obtained on instruments supported by the NIH Shared Instrumentation grant. The authors gratefully acknowledge Dr. Isaac Donkor (University of Tennessee) for useful discussions.
Published - ao7b01740.pdf
Supplemental Material - ao7b01740_si_001.pdf