Zoliflodacin: An oral spiropyrimidinetrione antibiotic for the treatment of Neisseria gonorrhoeae, including multi-drug resistant isolates.
2020
The CDC and World Health Organization have issued a list of priority pathogens for which there are dwindling therapeutic options, including antibiotic-resistant N. gonorrhoeae, for which novel, oral agents are urgently needed. Zoliflodacin, the first in a new class of antibacterial agents called the spiropyrimidinetriones, is being developed for the treatment of gonorrhea. It has a unique mode-of-inhibition against bacterial type II topoisomerases with binding sites in bacterial gyrase that are distinct from those of the fluoroquinolones. Zoliflodacin is bactericidal, with a low frequency of resistance and potent antibacterial activity against N. gonorrhoeae, including multi-drug resistant strains (MICs ranging from =0.002 - 0.25 microg/mL). Although being developed for the treatment of gonorrhea, zoliflodacin also has activity against Gram-positive, fastidious Gram-negative and atypical pathogens. A hollow-fiber infection model using S. aureus showed that that pharmacokinetic/pharmacodynamic (PK/PD) index of fAUC/MIC best correlated with efficacy in in vivo neutropenic thigh models in mice. This data and unbound exposure magnitudes derived from the thigh models were subsequently utilized in a surrogate pathogen approach to establish dose ranges for clinical development with N. gonorrhoeae. In preclinical studies, a wide safety margin supported progression to Phase 1 studies in healthy volunteers, which showed linear pharmacokinetics, good oral bioavailability and no significant safety findings. In a Phase 2 study, zoliflodacin was effective in treating gonococcal urogenital and rectal infections. In partnership with GARDP, zoliflodacin is currently being studied in a global Phase 3 clinical trial. Zoliflodacin represents a promising new therapy for drug resistant infections caused by N. gonorrhoeae.
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