NBTI 5463 is a novel bacterial type II topoisomerase inhibitor with Gram - 6 negative antibacterial activity and in vivo efficacy

30 The need for new antibiotics that address serious Gram-negative infections is well recognized. 31 Our effort in a series of novel bacterial type II topoisomerase inhibitors (designated as NBTIs) led 32 to the discovery of NBTI 5463, an agent with improved Gram-negative activity over other 33 NBTIs, in particular against Pseudomonas aeruginosa (F. Reck et al., submitted for publication). 34 In the present work, NBTI 5463 demonstrated promising activity against a broad range of Gram35 negative pathogens. In contrast to fluoroquinolones, the compound did not form a double-strand 36 DNA cleavable complex with E. coli DNA gyrase and DNA, but was a potent inhibitor of both 37 DNA gyrase and E. coli topoisomerase IV catalytic activities. In studies with P. aeruginosa, 38 NBTI 5463 was bactericidal. Resistant mutants arose at a low rate, and the mutations were found 39 exclusively in the nfxB gene, a regulator of the MexCD-OprJ efflux system. Levofloxacin 40 selected resistance mutations in GyrA did not result in decreased susceptibility to NBTI 5463. 41 Animal infection studies demonstrated that NBTI 5463 was efficacious in mouse models of lung, 42 thigh and ascending urinary tract infections. 43