Zoliflodacin

Zoliflodacin (development codes AZD0914 and ETX0914) is an experimental antibiotic that is being studied for the treatment of infection with Neisseria gonorrhoeae (gonorrhea). It has a novel mechanism of action which involves inhibition of bacterial type II topoisomerases. Zoliflodacin is being developed by Innoviva Specialty Therapeutics, and the drug has demonstrated clinical efficacy equivalent to ceftriaxone in Phase III clinical trials.

Susceptible bacteria
Zoliflodacin has shown in vitro activity against the following species of bacteria:


 * Staphylococcus aureus
 * Staphylococcus pyogenes
 * Streptococcus agalactiae
 * Streptococcus pneumoniae
 * Haemophilus influenzae
 * Moraxella catarrhalis
 * Mycoplasma pneumoniae
 * Neisseria gonorrhoeae
 * Chlamydia trachomatis
 * Mycoplasma genitalium

Mechanism of action
Zoliflodacin is primarily active against both Gram-positive, but has activity against fastidious Gram-negative bacteria. It functions by inhibiting DNA gyrase, an enzyme necessary to separate bacterial DNA, thereby inhibiting cell replication.

History
A high throughput screening campaign aimed at identifying compounds with whole cell antibacterial activity performed at Pharmacia & Upjohn identified compound PNU-286607, a progenitor of Zoliflodacin, as having the desired activity. Subsequent biological profiling of PNU-286607 showed that the compound inhibited DNA synthesis in susceptible bacteria, and analysis of mutants resistant to the compound's activity indicated that these compounds acted on DNA gyrase at a site distinct from that of the fluoroquinolone antibiotics.

Subsequent research at AstraZeneca led to the discovery that the nitroaromatic in PNU-286607 could be replaced with a fused benzisoxazole ring, which allowed for an exploration of different groups at the 3-position of the heterocycle. This work was continued at Entasis Pharmaceuticals where extensive optimization resulted in the discovery of ETX0914, which was renamed Zolifodacin in the course of its clinical development.