Abstract
Background: In an effort to identify a novel class of antibiotic for the treatment of infection by Gram-negative bacteria, the antimicrobial activity, pharmacokinetic profile and in vivo efficacy in murine models of E. coli infection were evaluated for the non-hydroxamic acid LpxC inhibitor FG- 630.
Results: FG-630 demonstrated an MIC against E. coli (ATCC 25922) of 1.0 μg/mL (4.0 μg/mL with 50% of FBS, 2.0 μg/mL with 20% rat urine). FG-630 showed activity against K. pneumoniae and other Enterobacteriaceae, including clinical isolates harboring plasmids containing the resistance genes mcr-1, ESBL, KPC, and NDM. FG-630 showed MIC of >128 μg/mL against S. aureus.
FG-630 displayed favorable PK parameters in mice with CL of 15.8 mL/min/Kg; Vd of 3.9 L/Kg, T1/2 of 3.5 hr and oral bioavailability of 49% when dosed at 0.67 mg/kg. When dosed at 60 mg/kg, a sustained urine exposure was evident, with a total of 3.8% of dose for IV and 2.1% of dose for PO over 12 hr, rendering a 55% oral bioavailability in urine.
In an murine IP sepsis model, comparing with vehicle control 9 hr post infection, FG-630 (60 mg/kg, IV) and Tigecycline (20 mg/kg, IV), dosed at 1 hr and 5 hr post infection, reduced Log10 CFU/mL counts of MDR E. coli (BAA-2469) in the abdomen by 5.55 and 5.88, respectively.
In a 5-day murine UTI infection model, FG-630 (60 mg/kg, q12h BID) and Ciprofloxacin (10 mg/kg, q12h BID) reduced susceptible E. coli (UTI98) Log10 CFU/mL counts in the kidneys by 3.91 and 3.01, respectively, the bladder by 3.18 and 2.45, respectively and the urine by 1.44 and 3.92, respectively. It is worth noting that at 15 mg/kg, FG-630 reduced bladder Log10 CFU/mL counts by 2.38.
Conclusion: FG-630 demonstrated in vitro antimicrobial activity against WT and MDR Enterobacteriaceae and favorable PK properties in mice. FG-630 significantly reduced CFU burden in the abdomens, kidneys, bladders and urine of mice in models of MDR IP sepsis and UTI.
a Forge Therapeutics Inc., San Diego, CA
b Evotec (UK), Manchester, United Kingdom
