AZD5099

AZD5099 potently inhibits purified S. aureus GyrB (IC₅₀ < 10 nM) and E. coli ParE bacterial type II topoisomerases^[1].
AZD5099 exhibits potent antibacterial activity against Gram-positive pathogens including MSSA (MIC = 0.03 μg/mL), MRSA, Streptococcus pyogenes, Streptococcus pneumoniae, and Enterococcus spp, its activity against wild-type Escherichia coli is weak, whereas potency is markedly enhanced in the efflux-deficient ΔtolC E. coli strain^[1].
AZD5099 (sub-lethal concentration) selectively inhibits DNA biosynthesis (10^3.6-fold reduction in ³H-thymidine incorporation) and secondary RNA biosynthesis (10^2.8-fold reduction in ³H-uridine incorporation) in S. aureus cultures, with no effect on protein or cell wall biosynthesis^[1].
AZD5099 (4× and 8× the concentration that prevented confluent bacterial growth) has very low spontaneous resistance frequencies (< 9.6 × 10^-10 in S. aureus and S. pneumoniae, ≤ 3.7 × 10^-9 in Enterococcus spp., 1.4 × 10^-7 to < 3.4 × 10^-10 in S. pyogenes), with resistant S. aureus variants exhibiting target-based gyrB mutations^[1].
AZD5099 exhibits greater than 10,000-fold selectivity for bacterial type II topoisomerases over human topoisomerase IIα, with an IC₅₀ > 50 µM against the human enzyme^[1].
AZD5099 (highest concentrations tested) is not mutagenic in preclinical in vitro assays including the Ames assay, mouse lymphoma micronucleus assay, and mouse lymphoma TK assay^[1].
AZD5099 (100 µM) does not inhibit hERG or other ion channels, providing a greater than 200-fold safety margin relative to predicted free C_max^[1].
AZD5099 (50 µM) does not inhibit human Cyp1A2, Cyp2C19, Cyp2C9, Cyp2D6, or Cyp3A4 enzymes, mitigating cytochrome P450-mediated drug-drug interaction risks^[1].
AZD5099 inhibits ATPase activity of human MRP2 and rat Mrp2 expressed in Sf9 cells, a trait associated with reduced in vivo clearance relative to transporter-activating analogs^[1].
AZD5099 potently inhibits Staphylococcus aureus gyrase with an IC₅₀ of 32 nM^[3].
AZD5099 inhibits Escherichia coli gyrase with an IC₅₀ of 0.760 μmol/L^[3].
AZD5099 (0.008-128 μg/mL; 18-24 h) inhibits the growth of Staphylococcus aureus (ATCC29213) with an MIC of 0.015 μg/mL^[3].
AZD5099 (0.008-128 μg/mL; 18-24 h) inhibits the growth of Escherichia coli (ATCC25922) with an MIC of 32 μg/mL^[3].
AZD5099 (25-400 nmol/L; 120 s association, 180 s dissociation) binds to Staphylococcus aureus GyrB24 with high affinity, exhibiting a K_D of 83.8 nmol/L^[3].
AZD5099 (0.008-128 μg/mL; 18-24 h) inhibits the growth of susceptible and resistant Gram-positive bacteria including Staphylococcus aureus (MRSA, MSSA, VISA), Staphylococcus epidermidis (MRSE, MSSE), Enterococcus faecalis, and Enterococcus faecium, with an MIC of 0.015 μg/mL for VISA strains and 0.03 μg/mL for most other strains, but is inactive against tested Gram-negative strains^[3].
AZD5099 (50-800 μmol/L; 24 h) shows significant mitochondrial toxicity in HepG2 cells, with an IC₅₀ < 200 μmol/L and complete damage at 400 μmol/L^[3].
AZD5099 potently inhibits Staphylococcus aureus DNA gyrase (IC₅₀ <10 nM) and Escherichia coli topoisomerase IV (IC₅₀ 73 nM), and exhibits antibacterial activity with MIC values of 0.036 μg/mL against Staphylococcus aureus, 24 μg/mL against wild-type Escherichia coli, and 0.94 μg/mL against Escherichia coli tolC mutant strain^[4].

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