TY - JOUR
T1 - Hit-to-Lead Identification and Validation of a Triaromatic Pleuromutilin Antibiotic Candidate
AU - Heidtmann, Christoffer V
AU - Fejer, Andreas R
AU - Stærk, Kristian
AU - Pedersen, Maria
AU - Asmussen, Marco G
AU - Hertz, Frederik B
AU - Prabhala, Bala K
AU - Frimodt-Møller, Niels
AU - Klitgaard, Janne K
AU - Andersen, Thomas E
AU - Nielsen, Carsten U
AU - Nielsen, Poul
PY - 2024/3/14
Y1 - 2024/3/14
N2 - Herein, we report the hit-to-lead identification of a drug-like pleuromutilin conjugate
16, based on a triaromatic hit reported in 2020. The lead arose as the clear candidate from a hit-optimization campaign in which Gram-positive antibacterial activity, solubility, and P-gp affinity were optimized. Conjugate
16 was extensively evaluated for its
in vitro ADMET performance which, apart from solubility, was overall on par with lefamulin. This evaluation included Caco-2 cell permeability, plasma protein binding, hERG inhibition, cytotoxicity, metabolism in microsomes and CYP3A4, resistance induction, and time-kill kinetics. Intravenous pharmacokinetics of
16 proved satisfactory in both mice and pigs; however, oral bioavailability was limited likely due to insufficient solubility. The
in vivo efficacy was evaluated in mice, systemically infected with
Staphylococcus aureus, where
16 showed rapid reduction in blood bacteriaemia. Through our comprehensive studies, lead
16 has emerged as a highly promising and safe antibiotic candidate for the treatment of Gram-positive bacterial infections.
AB - Herein, we report the hit-to-lead identification of a drug-like pleuromutilin conjugate
16, based on a triaromatic hit reported in 2020. The lead arose as the clear candidate from a hit-optimization campaign in which Gram-positive antibacterial activity, solubility, and P-gp affinity were optimized. Conjugate
16 was extensively evaluated for its
in vitro ADMET performance which, apart from solubility, was overall on par with lefamulin. This evaluation included Caco-2 cell permeability, plasma protein binding, hERG inhibition, cytotoxicity, metabolism in microsomes and CYP3A4, resistance induction, and time-kill kinetics. Intravenous pharmacokinetics of
16 proved satisfactory in both mice and pigs; however, oral bioavailability was limited likely due to insufficient solubility. The
in vivo efficacy was evaluated in mice, systemically infected with
Staphylococcus aureus, where
16 showed rapid reduction in blood bacteriaemia. Through our comprehensive studies, lead
16 has emerged as a highly promising and safe antibiotic candidate for the treatment of Gram-positive bacterial infections.
KW - Animals
KW - Anti-Bacterial Agents/therapeutic use
KW - Biological Availability
KW - Caco-2 Cells
KW - Diterpenes/pharmacology
KW - Humans
KW - Mice
KW - Microbial Sensitivity Tests
KW - Pleuromutilins
KW - Polycyclic Compounds/pharmacology
KW - Staphylococcal Infections/drug therapy
KW - Swine
U2 - 10.1021/acs.jmedchem.3c02153
DO - 10.1021/acs.jmedchem.3c02153
M3 - Journal article
C2 - 38385364
SN - 0022-2623
VL - 67
SP - 3692
EP - 3710
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 5
ER -