Zoliflodacin (development codes AZD0914 and ETX0914) is an experimental

antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting pathogenic bacteria, bacterial infections, and antibiotic medications are widely used in the therapy ...

that is being studied for the treatment of

antibiotic resistant Antimicrobial resistance (AMR or AR) occurs when microbes evolve mechanisms that protect them from antimicrobials, which are drugs used to treat infections. This resistance affects all classes of microbes, including bacteria (antibiotic resist ...

Neisseria gonorrhoeae ''Neisseria gonorrhoeae'', also known as ''gonococcus'' (singular) or ''gonococci'' (plural), is a species of Gram-negative diplococci bacteria first isolated by Albert Ludwig Sigesmund Neisser, Albert Neisser in 1879. An obligate human pathog ...

'' (

gonorrhea Gonorrhoea or gonorrhea, colloquially known as the clap, is a sexually transmitted infection (STI) caused by the bacterium ''Neisseria gonorrhoeae''. Infection may involve the genitals, mouth, or rectum. Gonorrhea is spread through sexual c ...

). It has a novel

mechanism of action In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical Drug interaction, interaction through which a Medication, drug substance produces its pharmacological effect. A mechanism of action usually includes mention o ...

which involves

inhibition Inhibitor or inhibition may refer to: Biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotransm ...

of bacterial

type II topoisomerase Type II topoisomerases are topoisomerases that cut both strands of the DNA helix simultaneously in order to manage DNA tangles and supercoils. They use the hydrolysis of ATP, unlike Type I topoisomerase. In this process, these enzymes change th ...

s. Zoliflodacin is being developed as part of a public-private partnership between Innoviva Specialty Therapeutics and the Global Antibiotic Research & Development Partnership (GARDP), and the drug has demonstrated clinical efficacy equivalent to

ceftriaxone Ceftriaxone, sold under the brand name Rocephin, is a third-generation cephalosporin antibiotic used for the treatment of a number of bacterial infections. These include middle ear infections, endocarditis, meningitis, pneumonia, bone and joi ...

Phase III clinical trials The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...

Susceptible bacteria

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

Staphylococcus aureus ''Staphylococcus aureus'' is a Gram-positive spherically shaped bacterium, a member of the Bacillota, and is a usual member of the microbiota of the body, frequently found in the upper respiratory tract and on the skin. It is often posi ...

* Staphylococcus pyogenes * Streptococcus agalactiae *

Streptococcus pneumoniae ''Streptococcus pneumoniae'', or pneumococcus, is a Gram-positive, spherical bacteria, hemolysis (microbiology), alpha-hemolytic member of the genus ''Streptococcus''. ''S. pneumoniae'' cells are usually found in pairs (diplococci) and do not f ...

Haemophilus influenzae ''Haemophilus influenzae'' (formerly called Pfeiffer's bacillus or ''Bacillus influenzae'') is a Gram-negative, Motility, non-motile, Coccobacillus, coccobacillary, facultative anaerobic organism, facultatively anaerobic, Capnophile, capnophili ...

Moraxella catarrhalis ''Moraxella catarrhalis'' is a fastidious, nonmotile, Gram-negative, aerobic, oxidase-positive diplococcus that can cause infections of the respiratory system, middle ear, eye, central nervous system, and joints of humans. It causes the in ...

* Mycoplasma pneumoniae *

Chlamydia trachomatis ''Chlamydia trachomatis'' () is a Gram-negative, Anaerobic organism, anaerobic bacterium responsible for Chlamydia infection, chlamydia and trachoma. ''C. trachomatis'' exists in two forms, an extracellular infectious elementary body (EB) and an ...

Mycoplasma genitalium ''Mycoplasma genitalium'' (also known as ''MG','' Mgen, or since 2018, ''Mycoplasmoides genitalium'') is a sexually transmitted, small and pathogenic bacterium that lives on the mucous epithelial cells of the urinary and genital tracts in ...

Pharmacology

Mechanism of action

Zoliflodacin is primarily active against both

Gram-positive In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall. The Gram stain is ...

, but has activity against fastidious

Gram-negative Gram-negative bacteria are bacteria that, unlike gram-positive bacteria, do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. Their defining characteristic is that their cell envelope consists ...

bacteria. It functions by inhibiting

DNA gyrase DNA gyrase, or simply gyrase, is an enzyme within the class of topoisomerase and is a subclass of Type II topoisomerases that reduces topological strain in an ATP dependent manner while double-stranded DNA is being unwound by elongating RNA-po ...

, 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 Pharmacia & Upjohn was a global pharmaceutical company formed by the merger of Sweden-based Pharmacia AB and the American company Upjohn in 1995. Today the remainder of the company is owned by Pfizer. In 1997, Pharmacia & Upjohn sold several b ...

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

at a site distinct from that of the

fluoroquinolone Quinolone antibiotics constitute a large group of broad-spectrum bacteriocidals that share a bicyclic core structure related to the substance 4-quinolone. They are used in human and veterinary medicine to treat bacterial infections, as well ...

antibiotics. Subsequent research at

AstraZeneca AstraZeneca plc () (AZ) is a British-Swedish multinational pharmaceutical and biotechnology company with its headquarters at the Cambridge Biomedical Campus in Cambridge, UK. It has a portfolio of products for major diseases in areas includi ...

led to the discovery that the nitroaromatic in PNU-286607 could be replaced with a fused

benzisoxazole 1,2-Benzisoxazole is an aromatic organic compound with a molecular formula C7H5NO containing a benzene-fused isoxazole ring structure. The compound itself has no common applications; however, functionalized benzisoxazoles and benzisoxazoyls have ...

ring, which allowed for an exploration of different groups at the 3-position of the

heterocycle A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different elements as members of its ring(s). Heterocyclic organic chemistry is the branch of organic chemistry dealing with the synthesis, proper ...

. 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.

References

{{reflist Experimental drugs Antibiotics 2-Oxazolidinones Benzisoxazoles Fluoroarenes Barbiturates Tetrahydroquinolines Morpholines Spiro compounds