The manuscript details the discovery of ETX0462, highlighting the importance of concurrent optimization of biochemical potency and drug penetration into the bacterial cells to identify structural elements critical for antimicrobial activity against multiple contemporary MDR Gram-negative and biothreat bacterial pathogens, including MDR Pseudomonas. Thanks to its innovative chemical design, the activity of ETX0462 is unaffected by all four Ambler classes of β-lactamases. Furthermore, ETX0462’s ability to permeate bacterial cells through multiple porins and inhibition of multiple penicillin-binding proteins (PBP) enzyme subtypes, results in low propensity for resistance emergence.
“To our knowledge, the novel lead optimization approach which led to ETX0462 is a first in antibiotic drug discovery,” commented
“I would like to congratulate the authors on the publication of this profile of ETX0462 in the prestigious scientific journal, Nature,” stated
Entasis is a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of novel antibacterial products to treat serious infections caused by multidrug-resistant Gram-negative bacteria. Entasis’ pathogen-targeted design platform has produced a pipeline of product candidates, including SUL-DUR (targeting Acinetobacter baumannii infections), zoliflodacin (targeting Neisseria gonorrhoeae infections), ETX0282CPDP (targeting Enterobacterales infections) and ETX0462 (targeting Pseudomonas infections). For more information, visit www.entasistx.com.
ETX0462 is a novel, first-in-class, diazabicyclooctane with antimicrobial activity against multidrug-resistant (MDR) Gram-negative and biothreat pathogens including, P. aeruginosa, K. pneumoniae, S. maltophilia, E. coli, B. anthracis, Y. pestis, F. tularensis and Burkholderia spp. Similar to β-lactam antibiotics, ETX0462 inhibits penicillin-binding proteins which are essential for bacterial cell wall biosynthesis, however, unlike β-lactam antibiotics, ETX0462 is unaffected by β-lactamase mediated resistance. ETX0462 is supported by CARB-X.
Source: Entasis Therapeutics Holdings Inc.