In vitro antibacterial activity of AZD0914, a new spiropyrimidinetrione DNA gyrase/topoisomerase inhibitor with potent activity against Gram-positive, fastidious Gram-Negative, and atypical bacteria.
AZD0914 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; this mechanism of inhibition differs from those of other marketed antibacterial compounds. AZD0914 stabilizes and arrests the cleaved covalent complex of gyrase with double-strand broken DNA under permissive conditions and thus blocks religation of the double-strand cleaved DNA to form fused circular DNA. Whereas this mechanism is similar to that seen with fluoroquinolones, it is mechanistically distinct. AZD0914 exhibited low frequencies of spontaneous resistance in S. aureus, and if mutants were obtained, the mutations mapped to gyrB. Additionally, no cross-resistance was observed for AZD0914 against recent bacterial clinical isolates demonstrating resistance to fluoroquinolones or other drug classes, including macrolides, β-lactams, glycopeptides, and oxazolidinones. AZD0914 was bactericidal in both minimum bactericidal concentration and in vitro time-kill studies. In in vitro checkerboard/synergy testing with 17 comparator antibacterials, only additivity/indifference was observed. The potent in vitro antibacterial activity (including activity against fluoroquinolone-resistant isolates), low frequency of resistance, lack of cross-resistance, and bactericidal activity of AZD0914 support its continued development.
Infection iMed, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA Michael.Huband@AstraZeneca.com.
Michael D
MD
Huband
Infection iMed, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA.
Patricia A
PA
Bradford
Infection iMed, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA.
Linda G
LG
Otterson
Infection iMed, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA.
Gregory S
GS
Basarab
Infection iMed, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA.
Amy C
AC
Kutschke
Infection iMed, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA.
Robert A
RA
Giacobbe
Infection iMed, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA.
Sara A
SA
Patey
Infection iMed, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA.
Richard A
RA
Alm
Infection iMed, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA.
Michele R
MR
Johnstone
Infection iMed, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA.
Marie E
ME
Potter
Infection iMed, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA.
Paul F
PF
Miller
Infection iMed, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA.
John P
JP
Mueller
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001295:Atypical Bacterial Forms / Q000187:drug effects; D001463:Barbiturates / Q000494:pharmacology*; D027081:DNA Gyrase / Q000187:drug effects*; D024881:Drug Resistance, Bacterial; D024841:Fluoroquinolones / Q000494:pharmacology; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D007555:Isoxazoles; D008826:Microbial Sensitivity Tests; D009025:Morpholines; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology*; D023303:Oxazolidinones; D013141:Spiro Compounds / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D001463:Barbiturates; D024841:Fluoroquinolones; D007555:Isoxazoles; D009025:Morpholines; D019384:Nucleic Acid Synthesis Inhibitors; D023303:Oxazolidinones; D013141:Spiro Compounds; D059005:Topoisomerase II Inhibitors; D027081:DNA Gyrase; C000599190:zoliflodacin