AZD5099

AZD5099 is an orally effective pyrrole amide inhibitor and antibacterial agent. AZD5099 shows over 10000-fold higher selectivity for bacterial type II topoisomerases than for human topoisomerase IIα, with a IC₅₀ value of 0.032 μmol/L against Staphylococcus aureus GyrB, a IC₅₀ of 0.760 μmol/L against Escherichia coli GyrB, a IC₅₀ of 73 nM against Escherichia coli ParE, a K_d of 83.8 nmol/L for Staphylococcus aureus GyrB, and a IC₅₀ of >50 μM against human topoisomerase IIα. AZD5099 inhibits rat Mrp2 ATPase activity, competitively binds to the ATP-binding site of bacterial type II topoisomerases, blocks enzyme activity, reduces bacterial DNA and RNA synthesis, disrupts DNA replication and transcription processes, and induces mitochondrial toxicity. AZD5099 exhibits activity against Gram-positive bacteria, fastidious Gram-negative bacteria and drug-resistant strains, reduces bacterial loads in mouse infection models, and has a low spontaneous resistance frequency. AZD5099 can be used in studies related to infections caused by Gram-positive bacteria and fastidious Gram-negative bacteria, methicillin-resistant Staphylococcus aureus infections, Streptococcus pneumoniae pulmonary infections, as well as Staphylococcus aureus and Escherichia coli infections^[1][2][3][4]. In Vitro: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]. In Vivo:AZD5099 (3-100 mg/kg) demonstrates dose-dependent efficacy against S. aureus MSSA in a neutropenic mouse thigh infection model, with a 4-log reduction in CFU relative to controls at the 30 mg/kg dose^[1].
AZD5099 exhibits high in vivo antibacterial activity against Streptococcus pneumoniae in a mouse lung infection model^[2].
AZD5099 (10 mg/kg; i.g.; single dose) provides 100% survival protection in MRSA-induced sepsis in mice, with an ED₅₀ of 7.5 mg/kg^[3].