zoliflodacin (ETX0914) / Global Antibiotic Research and Development Partnership, Innoviva - LARVOL DELTA

Global genomic and antimicrobial resistance profiling of Neisseria gonorrhoeae: Insights from whole genome sequencing and minimum inhibitory concentration analysis. (PubMed, PLoS Negl Trop Dis) - "Efflux pump systems are key to N. gonorrhoeae resistance and adaptability. Regional MIC variations indicate that local antibiotic use shapes resistance patterns. The high resistance to penicillin and spectinomycin highlights the need for alternative treatments, whereas zoliflodacin and fluoroquinolones remain effective but require monitoring. This study emphasizes global AMR surveillance, novel therapies, and targeted antimicrobial stewardship to address multidrug-resistant infections."

Journal • Infectious Disease

Noncytotoxic polymyxin derivatives enhance antibiotic action against multidrug-resistant Gram-negative bacteria. (PubMed, Antimicrob Agents Chemother) - "Compound 1 extended the activity spectrum of rifampicin, zoliflodacin, and pristinamycin by lowering the minimum inhibitory concentrations of these antibiotics below their interpretative susceptibility breakpoints in MDR Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae. Notably, the novel combination of zoliflodacin, a first-in-class antibiotic in phase III trials for gonorrhea, and compound 1 exhibited potent bactericidal activity in MDR P. aeruginosa and A. baumannii."

Journal • Infectious Disease • Pneumonia

In Vitro Activity of Zoliflodacin against Neisseria gonorrhoeae Isolates Collected in 2022 from The United States (IDWeek 2025) - No abstract available

Preclinical • Infectious Disease

Subgroup Analyses of Microbiological Cure Rates by Baseline Zoliflodacin MIC and Susceptibility to Ciprofloxacin in Participants from the Global Zoliflodacin Phase 3 Randomized Controlled Trial (IDWeek 2025) - No abstract available

Clinical • P3 data • Infectious Disease

Association of Sex Assigned at Birth and Sexual Orientation with Antimicrobial Susceptibility of Baseline Neisseria gonorrhoeae Isolates from Participants Recruited in the Global Zoliflodacin Phase 3 Randomized Controlled Trial (IDWeek 2025) - No abstract available

Clinical • P3 data • Infectious Disease

Antimicrobial resistance in Neisseria gonorrhoeae in nine sentinel countries within the World Health Organization Enhanced Gonococcal Antimicrobial Surveillance Programme (EGASP), 2023: a retrospective observational study. (PubMed, Lancet Reg Health West Pac) - "Minimum inhibitory concentrations (MICs, mg/L) values were determined for ceftriaxone, cefixime, azithromycin, gentamicin, and ciprofloxacin using Etest (bioMérieux). Novel antimicrobials for gonorrhoea treatment are critical; zoliflodacin and gepotidacin are promising. WHO, Global Fund."

Journal • Observational data • Retrospective data • Infectious Disease

Susceptibility of Neisseria gonorrhoeae to Zoliflodacin and Quinolones in Hyogo Prefecture, Japan. (PubMed, Pathogens) - "In addition to ZFD, we investigated the susceptibility of N. gonorrhoeae strains to ceftriaxone (CTRX), ciprofloxacin (CPFX), garenoxacin (GRNX), and sitafloxacin (STFX). ZFD showed potent antimicrobial activity against N. gonorrhoeae strains that are highly resistant to quinolones. It may become a new option in the treatment of gonococcal infections."

Journal • Infectious Disease

TXA15054 - A Novel Narrow Spectrum Oral Antibiotic Against Neisseria Gonorrhoeae (ASM Microbe 2025) - "In this context, TAXIS Pharmaceuticals has successfully developed novel narrow spectrum inhibitors that specifically target bacterial dihydrofolate reductase (DHFR) while avoiding any significant engagement with human-DHFR (3).While inactive against other Gram-positive and Gram-negative pathogens, TXA15054 is potent against multiple Neisseria gonorrhoeae (Ng) strains, including ceftriaxone-resistant strains (WHO-X, WHO-Y, WHO-Z), azithromycin-, ciprofloxacin-, and tetracycline-resistant CDC isolates, with impressive low MIC values ranging from 0.031 to 0.004 μg/mL...TXA15054 showed minimal impact against Lactobacillus species in the urogenital tract unlike ceftriaxone, azithromycin and clinical trial candidates, zoliflodacin and gepotidacin...Cell. 2020 Jun 25; 181(7):1518-1532."

Infectious Disease • Vaginitis • DHFR

Potential of Established and Novel Antibacterials Against Acinetobacter baumannii Gyrase and Topoisomerase IV (ASM Microbe 2025) - "Thus, we assessed the effects of two novel antibacterials, gepotidacin (a triazaacenaphthelene, TAA) and zoliflodacin (a spiropyrimidinetrione, SPT), on the activities of the A. baumannii type II topoisomerases. Finally, gepotidacin displayed potent inhibition of the catalytic activity of both WT and mutant gyrase/topoisomerase IV (IC50: WT gyrase ≈ 0.9 µM, GyrAS80L ≈ 0.3 µM, WT topo IV ≈ 0.4 µM; ParCS84L ≈ 0.06 µM). Results suggest that these new classes of antibacterials maybe useful for treating FQ-resistant A. baumannii infections."

Infectious Disease

Effects of Clinically Relevant Antibacterial Agents on Type II Topoisomerases from Pseudomonas aeruginosa (ASM Microbe 2025) - "Gepotidacin, a novel bacterial topoisomerase inhibitor (NBTI) and zoliflodacin, a spiropyrimidinetrione (SPT) offer promising alternatives by targeting type II topoisomerases via mechanisms distinct from fluoroquinolones and avoiding common fluoroquinolone resistance mutations...Two fluoroquinolones, ciprofloxacin and moxifloxacin, displayed similar DNA cleavage activity (CC50 ~3.0 µM, 30% DNA cleavage) but moxifloxacin was more potent in decatenation assays (IC50 ~19.5 µM vs 28.7 µM)...These compounds are currently being evaluated against gyrase and fluoroquinolone-resistant enzymes. The finding that gepotidacin exhibits potent in vitro activity, with lower CC50 and IC50 values compared to fluoroquinolones, supports its potential as a therapeutic option for drug-resistant P. aeruginosa infections."

Clinical • Infectious Disease

GyrA and GyrB-Mediated Zoliflodacin and Ciprofloxacin Cross-Resistance and In Vitro Fitness Implications in Neisseria gonorrhoeae (ASM Microbe 2025) - "The fitness cost incurred by GyrBD429N-mediated zoliflodacin resistance on the background of GyrAS91F-mediated ciprofloxacin resistance indicates a barrier to developing resistance to both antibiotics. Our study emphasizes the importance of understanding resistance dynamics and fitness costs to guide the clinical use of zoliflodacin and mitigate resistance emergence."

Preclinical • Infectious Disease

Innoviva Specialty Therapeutics Receives FDA New Drug Application Acceptance for Zoliflodacin, a First-in-Class Oral Antibiotic for Uncomplicated Gonorrhea in Adults (ANSA) - "Innoviva Specialty Therapeutics, Inc., a subsidiary of Innoviva, Inc...announced that the US Food and Drug Administration (FDA) has accepted its New Drug Application (NDA) for zoliflodacin, the investigational first-in-class, single dose, spiropyrimidinetrione oral antibiotic for the treatment of uncomplicated gonorrhea in adults and pediatric patients 12 years and older. If approved, zoliflodacin would be the first new antibiotic for treating gonorrhea in decades....The U.S. FDA has granted zoliflodacin a Qualified Infectious Disease Product (QIDP) designation. This designation allows it to benefit from FDA Priority Review, and Extended Market Exclusivity."

FDA approval • Priority review • Infectious Disease

An overview of potential combinations therapies with ceftriaxone as a treatment for gonorrhea. (PubMed, Expert Rev Anti Infect Ther) - "Of these 16 antimicrobials, we reject antimicrobials such as fosfomycin due to poor clinical efficacy and tigecycline due to its considerably longer half-life which would likely select for tetracycline resistance. The most promising agents for combination with ceftriaxone are zoliflodacin, delafloxacin, sitafloxacin, eravacycline and possibly gepotidacin and gentamicin. Clinical studies should be conducted to evaluate the efficacy of these combinations on the eradication of N. gonorrhoeae and their impact on AMR in N. gonorrhoeae and other bacterial species."

Journal • Review • Infectious Disease

In-vitro Activities of Zoliflodacin and Solithromycin Against Neisseria gonorrhoeae Isolates from Korea. (PubMed, Ann Lab Med) - "Most isolates (94.8%, 237/250) demonstrated non-susceptibility to penicillin G, tetracycline, and ciprofloxacin, and susceptibility to ceftriaxone and spectinomycin was substantially high. Zoliflodacin and solithromycin demonstrated significant in-vitro activity against multidrug-resistant N. gonorrhoeae isolates, and zoliflodacin has shown non-inferiority to ceftriaxone/azithromycin dual therapy in a clinical phase 3 trial. Collectively, our findings highlight the potential of zoliflodacin as a novel therapeutic agent for gonococcal infections, particularly in the context of rising multidrug resistance, and highlight the need for continued surveillance and development of alternative antimicrobial strategies."

Journal • Preclinical • Infectious Disease

High susceptibility to the novel antimicrobial zoliflodacin among Neisseria gonorrhoeae isolates in eight WHO Enhanced Gonococcal Antimicrobial Surveillance Programme countries in three WHO regions, 2021-2024. (PubMed, IJID Reg) - "We show a high susceptibility to zoliflodacin internationally, including against ceftriaxone- and azithromycin-resistant gonococcal strains. Our findings support the continued clinical development of zoliflodacin as a treatment for gonorrhea, although cautious and monitored introduction and continuous international resistance surveillance are imperative."

Journal • Infectious Disease

Evidence of reinfection and no emergence of resistance following a single oral 3g dose of zoliflodacin demonstrated by whole-genome sequencing (WGS) in a global Phase 3 randomised controlled trial (RCT) for treatment of uncomplicated gonorrhoea (ESCMID Global 2025) - No abstract available

Clinical • P3 data • Whole genome sequencing • Infectious Disease

How Do Gepotidacin and Zoliflodacin Stabilize DNA-Cleavage Complexes with Bacterial Type IIA Topoisomerases? 2. A Single Moving Metal Mechanism. (PubMed, Int J Mol Sci) - "Although the proposed mechanism is consistent with published data, it is not proven and other mechanisms have been proposed. Finally, how such mechanisms can be experimentally distinguished is considered."

Journal • Psychiatry

In vitro evolution of ciprofloxacin resistance in Neisseria commensals and derived mutation population dynamics in natural Neisseria populations. (PubMed, FEMS Microbiol Lett) - "Additionally, we tested for zoliflodacin cross-resistance in evolved strain lines and found 6 lineages with elevated zoliflodacin minimum inhibitory concentrations. Finally, to interrogate the likelihood of experimentally derived mutations emerging and contributing to resistance in natural Neisseria, we used a population-based approach and identified GyrA 91I as a substitution circulating within commensal Neisseria populations and ParC 85C in a single gonococcal isolate. A small cluster of gonococcal isolates shared commensal alleles at parE, suggesting recent cross-species recombination events."

Journal • Preclinical • Gene Therapies • Infectious Disease • MTRR

Recommendations for the optimal introduction of novel antibiotics to treat uncomplicated gonorrhoea in the face of increasing antimicrobial resistance: a case study with zoliflodacin. (PubMed, BMC Glob Public Health) - "Zoliflodacin, given as a single dose for uncomplicated urogenital gonorrhoea, recently demonstrated non-inferiority to ceftriaxone plus azithromycin and safety in a phase 3 randomised controlled trial. Recommendations from the expert group included: the generation of evidence for the role of a drug like zoliflodacin in clinical treatment failures; the need for additional antimicrobial resistance surveillance; investigation of the role of novel diagnostic approaches, such as point-of-care tests, to improve stewardship; study of preferences and values among the population in need; and modelling of the emergence of N. gonorrhoeae resistance and transmission in different scenarios. Forthcoming World Health Organization (WHO) global guidelines could outline recommendations for a new oral antibiotic like zoliflodacin based on existing evidence, and rational approaches for certain populations or use cases, while the evidence base is further strengthened."

Journal • Human Immunodeficiency Virus • Infectious Disease

Pharmacometric Analyses to Support Dose Selection of Zoliflodacin, a First-in-Class Oral Antibiotic Being Developed for the Treatment of Uncomplicated Gonorrhea (IDWeek 2024) - No abstract available

Infectious Disease

In Vitro Activity of Zoliflodacin Against Baseline Neisseria gonorrhoeae Isolates from US Participants in a Global Phase 3 Randomized Controlled Trial (IDWeek 2024) - No abstract available

P3 data • Preclinical • Infectious Disease

Zoliflodacin: Addressing a growing global threat through a novel public-private development partnership (IDWeek 2024) - No abstract available

Clinical • Human Immunodeficiency Virus • Infectious Disease

Alternative drugs for the treatment of gonococcal infections: old and new. (PubMed, Expert Rev Anti Infect Ther) - "These include aztreonam, ertapemen, and fosfomycin. New oral drugs zoliflodacin and gepotidacin are in late clinical development, but there are concerns regarding their effectiveness for extragenital infections and the development of resistance...Among older antibiotics, ertapenem shows the most potential as an alternative but shares the same administration drawbacks as ceftriaxone...Phase 3 trial results have not been made available except through press releases, which perpetuates concerns. Understanding pharmacokinetic and pharmacodynamic profiles of antibiotics will be key in optimizing future treatment recommendations."

Journal • Review • Infectious Disease • Otorhinolaryngology

Assessing novel partner antimicrobials to protect ceftriaxone against gonococcal resistance: An in vitro evaluation. (PubMed, Int J STD AIDS) - "The low MICs of zoliflodacin and pristinamycin for the three ceftriaxone-resistant strains suggest that these antimicrobials could be used as partner drugs with ceftriaxone to reduce the probability of ceftriaxone resistance spreading in areas with a high prevalence of ceftriaxone resistance."

Journal • Preclinical • Infectious Disease

Interactions between Zoliflodacin and Neisseria gonorrhoeae Gyrase and Topoisomerase IV: Enzymological Basis for Cellular Targeting. (PubMed, ACS Infect Dis) - "Finally, when compared to zoliflodacin, the novel SPT H3D-005722 induced more balanced double-stranded DNA cleavage with gyrase and topoisomerase IV from N. gonorrhoeae, Escherichia coli, and Bacillus anthracis. This finding suggests that further development of the SPT class could yield compounds with a more balanced targeting against clinically important bacterial infections."

Journal • Infectious Disease