Zoliflodacin(CAS 1620458-09-4), also known as AZD0914 and ETX0914, is a new spiropyrimidinetrione bacterial DNA gyrase/topoisomerase inhibitor with potent in vitro antibacterial activity against key Gram-positive (Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes, and Streptococcus agalactiae), fastidious Gram-negative (Haemophilus influenzae and Neisseria gonorrhoeae), atypical (Legionella pneumophila), and anaerobic (Clostridium difficile) bacterial species, including isolates with known resistance to fluoroquinolones. AZD0914 works via inhibition of DNA biosynthesis and accumulation of double-strand cleavages.
1. J Antimicrob Chemother. 2018 May 1;73(5):1291-1294. doi: 10.1093/jac/dky022.
In vitro activity of zoliflodacin (ETX0914) against macrolide-resistant, fluoroquinolone-resistant and antimicrobial-susceptible Mycoplasma genitalium strains.
Damião Gouveia AC(1), Unemo M(2), Jensen JS(1).
(1)Research Unit for Reproductive Tract Microbiology, Statens Serum Institut, Copenhagen, Denmark. (2)WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
Background: Mycoplasma genitalium is estimated to be the second most common cause of bacterial sexually transmitted infection in Europe. It is of increasing public health concern due to the rapid development of resistance to different antimicrobial classes, including the preferred first- and second-line treatments azithromycin and moxifloxacin. Thus, new antimicrobial agents are urgently needed, especially for the treatment of MDR strains.
Methods: The in vitro activity of the new spiropyrimidinetrione zoliflodacin against 47 M. genitalium strains was assessed by growing M. genitalium in Vero cell culture and measuring growth by quantitative PCR. The collection included 34 moxifloxacin-susceptible (MIC <1 mg/L) and 13 moxifloxacin-resistant (MIC ≥1 mg/L) strains. Twenty-three of the strains were azithromycin resistant (MIC ≥16 mg/L) and 12 of these strains were MDR.
Results: Only one (2.1%) strain with substantially increased MIC (4 mg/L) and potential resistance to zoliflodacin was found. Zoliflodacin was overall more potent than moxifloxacin (P = 0.009) and no cross-resistance was observed between the two drug classes of topoisomerase II inhibitors. Differences in the MICs of zoliflodacin and azithromycin were not statistically significant; however, 23 (48.9%) compared with potentially 1 (2.1%) of the strains were resistant to azithromycin and zoliflodacin, respectively.
Conclusions: Zoliflodacin is a promising candidate for the treatment of M. genitalium and it is important to further develop and evaluate this drug.
2. Antimicrob Agents Chemother. 2018 Dec 21;63(1). pii: e01808-18. doi: 10.1128/AAC.01808-18. Print 2019 Jan.
Single-Dose Pharmacokinetics, Excretion, and Metabolism of Zoliflodacin, a Novel Spiropyrimidinetrione Antibiotic, in Healthy Volunteers.
O'Donnell J(1), Lawrence K(2), Vishwanathan K(3), Hosagrahara V(4), Mueller JP(5).
(1)Entasis Therapeutics, Inc., Waltham, Massachusetts, USA. (2)Tetraphase Pharmaceuticals, Watertown, Massachusetts, USA. (3)Clinical Pharmacology, AstraZeneca Pharmaceuticals, Waltham, Massachusetts, USA. (4)EMD Serono, Billerica, Massachusetts, USA. (5)Entasis Therapeutics, Inc., Waltham, Massachusetts, USA [email protected]
Zoliflodacin is a novel spiropyrimidinetrione with activity against bacterial type II topoisomerases that inhibits DNA biosynthesis and results in accumulation of double-strand cleavages in bacteria. We report results from two phase 1 studies that investigated the safety, tolerability, and pharmacokinetics (PK) of zoliflodacin and absorption, distribution, metabolism, and excretion (ADME) after single doses in healthy volunteers. In the single ascending dose study, zoliflodacin was rapidly absorbed, with a time to maximum concentration of drug in serum (T max) between 1.5 and 2.3 h. Exposure increased dose proportionally up to 800 mg and less than dose proportionally between 800 and 4,000 mg. Urinary excretion of unchanged zoliflodacin was <5.0% of the total dose. In the fed state, absorption was delayed (T max, 4 h), accompanied by an increase in the area under the concentration-time curve (AUC) at 1,500- and 3,000-mg doses. In the ADME study (3,000 mg orally), the PK profile of zoliflodacin had exposure (AUC and maximum concentration of drug in serum [C max]) similar to that of the ascending dose study and a median T max of 2.5 h. A total of 97.8% of the administered radioactivity was recovered in excreta, with urine and fecal elimination accounting for approximately 18.2% and 79.6% of the dose, respectively. The major clearance pathway was via metabolism and elimination in feces with low urinary recovery of unchanged drug (approximately 2.5%) and metabolites accounting for 56% of the dose excreted in the feces. Zoliflodacin represented 72.3% and metabolite M3 accounted for 16.4% of total circulating radioactivity in human plasma. Along with the results from these studies and based upon safety, PK, and PK/pharmacodynamics targets, a dosage regimen was selected for evaluation in a phase 2 study in urogenital gonorrhea. (The studies discussed in this paper have been registered at ClinicalTrials.gov under identifiers NCT01929629 and NCT02298920.).
3. Antimicrob Agents Chemother. 2019 Sep 23. pii: AAC.01479-19. doi: 10.1128/AAC.01479-19. [Epub ahead of print]
High in vitro susceptibility to the first-in-class spiropyrimidinetrione zoliflodacin among consecutive clinical Neisseria gonorrhoeae isolates from Thailand (2018) and South Africa (2015-2017).
Jacobsson S(1), Kularatne R(2), Kittiyaowamarn R(3), Maseko V(2), Paopang P(3), Sangprasert P(3), Sirivongrangson P(4), Piddock L(5), Wi T(6), Alirol E(5), Unemo M(7).
(1)WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden. (2)Centre for HIV & STIs, National Institute for Communicable Diseases, National Health Laboratory Service, Johannesburg, South Africa. (3)Bangrak STI Center, Bureau of AIDs TB and STIs, Department of Disease Control, Ministry of Public Health, Bangkok, Thailand. (4)Department of Disease Control, Ministry of Public Health, Bangkok, Thailand. (5)Global Antibiotic Research & Development Partnership (GARDP), Geneva, Switzerland. (6)Department of Reproductive Health, World Health Organization, Geneva, Switzerland. (7)WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden [email protected]
We evaluated the in vitro susceptibility to the first-in-class spiropyrimidinetrione zoliflodacin among recent consecutive clinical Neisseria gonorrhoeae isolates cultured in Thailand (n=99; 2018) and South Africa (n=100; 2015-2017). Zoliflodacin was highly active in vitro against all tested isolates (MIC range: 0.004-0.25; MIC50: 0.064, MIC90: 0.125 μg/ml), with no cross-resistance to any of the seven comparator antimicrobials. Our data support the initiation of the global zoliflodacin phase 3 randomized controlled clinical trial for uncomplicated gonorrhea.