title: Discovery of a novel class of boron-based antibacterials with activity against gram-negative bacteria.
abstract: Gram-negative bacteria cause approximately 70% of the infections in intensive care units. A growing number of bacterial isolates responsible for these infections are resistant to currently available antibiotics and to many in development. Most agents under development are modifications of existing drug classes, which only partially overcome existing resistance mechanisms. Therefore, new classes of Gram-negative antibacterials with truly novel modes of action are needed to circumvent these existing resistance mechanisms. We have previously identified a new a way to inhibit an aminoacyl-tRNA synthetase, leucyl-tRNA synthetase (LeuRS), in fungi via the oxaborole tRNA trapping (OBORT) mechanism. Herein, we show how we have modified the OBORT mechanism using a structure-guided approach to develop a new boron-based antibiotic class, the aminomethylbenzoxaboroles, which inhibit bacterial leucyl-tRNA synthetase and have activity against Gram-negative bacteria by largely evading the main efflux mechanisms in Escherichia coli and Pseudomonas aeruginosa. The lead analogue, AN3365, is active against Gram-negative bacteria, including Enterobacteriaceae bearing NDM-1 and KPC carbapenemases, as well as P. aeruginosa. This novel boron-based antibacterial, AN3365, has good mouse pharmacokinetics and was efficacious against E. coli and P. aeruginosa in murine thigh infection models, which suggest that this novel class of antibacterials has the potential to address this unmet medical need.
authors.affiliation: Anacor Pharmaceuticals Inc., Palo Alto, CA, USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Hernandez
authors.forename: Thibaut
authors.initials: T
authors.lastname: Crépin
authors.forename: Andrés
authors.initials: A
authors.lastname: Palencia
authors.forename: Stephen
authors.initials: S
authors.lastname: Cusack
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Akama
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Baker
authors.forename: Wei
authors.initials: W
authors.lastname: Bu
authors.forename: Lisa
authors.initials: L
authors.lastname: Feng
authors.forename: Yvonne R
authors.initials: YR
authors.lastname: Freund
authors.forename: Liang
authors.initials: L
authors.lastname: Liu
authors.forename: Maliwan
authors.initials: M
authors.lastname: Meewan
authors.forename: Manisha
authors.initials: M
authors.lastname: Mohan
authors.forename: Weimin
authors.initials: W
authors.lastname: Mao
authors.forename: Fernando L
authors.initials: FL
authors.lastname: Rock
authors.forename: Holly
authors.initials: H
authors.lastname: Sexton
authors.forename: Anita
authors.initials: A
authors.lastname: Sheoran
authors.forename: Yanchen
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yong-Kang
authors.initials: YK
authors.lastname: Zhang
authors.forename: Yasheen
authors.initials: Y
authors.lastname: Zhou
authors.forename: James A
authors.initials: JA
authors.lastname: Nieman
authors.forename: Mahipal Reddy
authors.initials: MR
authors.lastname: Anugula
authors.forename: El Mehdi
authors.initials: el M
authors.lastname: Keramane
authors.forename: Kingsley
authors.initials: K
authors.lastname: Savariraj
authors.forename: D Shekhar
authors.initials: DS
authors.lastname: Reddy
authors.forename: Rashmi
authors.initials: R
authors.lastname: Sharma
authors.forename: Rajendra
authors.initials: R
authors.lastname: Subedi
authors.forename: Rajeshwar
authors.initials: R
authors.lastname: Singh
authors.forename: Ann
authors.initials: A
authors.lastname: O'Leary
authors.forename: Nerissa L
authors.initials: NL
authors.lastname: Simon
authors.forename: Peter L
authors.initials: PL
authors.lastname: De Marsh
authors.forename: Shazad
authors.initials: S
authors.lastname: Mushtaq
authors.forename: Marina
authors.initials: M
authors.lastname: Warner
authors.forename: David M
authors.initials: DM
authors.lastname: Livermore
authors.forename: M R K
authors.initials: MR
authors.lastname: Alley
authors.forename: Jacob J
authors.initials: JJ
authors.lastname: Plattner
mesh_terms: D000604:Amino Acyl-tRNA Synthetases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D001896:Boron Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology; D005260:Female; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy* / Q000382:microbiology; D006801:Humans; D007930:Leucine / Q000378:metabolism; D051379:Mice; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000201:enzymology; D013329:Structure-Activity Relationship; D013848:Thigh / Q000382:microbiology; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001896:Boron Compounds; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases; C063912:carbapenemase; D000604:Amino Acyl-tRNA Synthetases; D007930:Leucine