P2568: FPI-2119 Bactericidal activity and resistance selection in Pseudomonas aeruginosa
1Indiana University Bloomington, IN, USA; 2Fedora Pharmaceuticals Inc., Edmonton, Alberta, Canada.
Background: FPI-2119 is a newly developed synthetic derivative of lactivicin (LTV), a non-β-lactam compound that inactivates penicillin-binding proteins (PBPs) and exhibits bactericidal activity against Pseudomonas aeruginosa and other Gram-negative pathogens.
Methods: P. aeruginosa ATCC 27853 was evaluated with FPI-2119 using minimum inhibitory concentration (MIC) and time-kill assays (TKA) following CLSI guidelines. The frequency of resistance (FOR) was assessed on agar plates after 24 hours by single-step selection with an inoculum of 2x10⁸ CFU/ml. FPI-2119 MICs for colonies isolated from lung tissues of mice infected with P. aeruginosa ATCC 27853 and treated with various regimens of FPI-2119 were also determined. Persister strains obtained from the TKA and FOR studies were analyzed for basal β-lactamase activity by measuring nitrocefin hydrolysis in cell extracts; growth rates were monitored spectrophotometrically and compared to those of wild-type (WT).
Results: FPI-2119 exhibited concentration-dependent bactericidal killing (decrease ≥3 log10 CFU/mL) against P. aeruginosa ATCC 27853 at 32X MIC after 6h. FPI-2119 MICs of persisters from the TKA study showed only 2-4 fold increases (1-2 µg/mL) compared to the parent strain (MIC 0.5 µg/mL), suggesting reversion to WT after subculture on drug-free media. Similarly, FPI-2119 MICs of strains isolated from mice lung tissues infected with P. aeruginosa ATCC 27583 and treated with FPI-2119 showed little to no increase in MIC (MICRange 1-4 µg/mL vs 0.5 µg/mL) suggesting low rates of resistance selection in vivo. Low frequency of resistance (<1.8E-09 to 2.6E-08) was recorded in single step selection studies at 8X-32X MIC. Persisters from TKA and FOR studies exhibited basal level AmpC β-lactamase production. At stationary phase, persisters attained only 0.6-fold the cell density compared to WT.
Conclusions: The microbiological properties of FPI-2119 included bactericidal activity and a low propensity to select for resistance in P. aeruginosa. Persisters isolated from the TKA, FOR and lung infection studies reverted to WT phenotypes. Impaired fitness for TKA and FOR persisters was also observed. These results support advancement of FPI-2119 as a promising candidate for further development.
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