title: Synthesis and spectrum of the neoglycoside ACHN-490.
abstract: ACHN-490 is a neoglycoside, or "next-generation" aminoglycoside (AG), that has been identified as a potentially useful agent to combat drug-resistant bacteria emerging in hospitals and health care facilities around the world. A focused medicinal chemistry campaign produced a collection of over 400 sisomicin analogs from which ACHN-490 was selected. We tested ACHN-490 against two panels of Gram-negative and Gram-positive pathogens, many of which harbored AG resistance mechanisms. Unlike legacy AGs, ACHN-490 was active against strains expressing known AG-modifying enzymes, including the three most common such enzymes found in Enterobacteriaceae. ACHN-490 inhibited the growth of AG-resistant Enterobacteriaceae (MIC(90), ≤4 μg/ml), with the exception of Proteus mirabilis and indole-positive Proteae (MIC(90), 8 μg/ml and 16 μg/ml, respectively). ACHN-490 was more active alone in vitro against Pseudomonas aeruginosa and Acinetobacter baumannii isolates with AG-modifying enzymes than against those with altered permeability/efflux. The MIC(90) of ACHN-490 against AG-resistant staphylococci was 2 μg/ml. Due to its promising in vitro and in vivo profiles, ACHN-490 has been advanced into clinical development as a new antibacterial agent.
authors.affiliation: Achaogen, Inc., 7000 Shoreline Court, South San Francisco, CA 94080, USA.
authors.forename: James B
authors.initials: JB
authors.lastname: Aggen
authors.forename: Eliana S
authors.initials: ES
authors.lastname: Armstrong
authors.forename: Adam A
authors.initials: AA
authors.lastname: Goldblum
authors.forename: Paola
authors.initials: P
authors.lastname: Dozzo
authors.forename: Martin S
authors.initials: MS
authors.lastname: Linsell
authors.forename: Micah J
authors.initials: MJ
authors.lastname: Gliedt
authors.forename: Darin J
authors.initials: DJ
authors.lastname: Hildebrandt
authors.forename: Lee Ann
authors.initials: LA
authors.lastname: Feeney
authors.forename: Aya
authors.initials: A
authors.lastname: Kubo
authors.forename: Rowena D
authors.initials: RD
authors.lastname: Matias
authors.forename: Sara
authors.initials: S
authors.lastname: Lopez
authors.forename: Marcela
authors.initials: M
authors.lastname: Gomez
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Wlasichuk
authors.forename: Raymond
authors.initials: R
authors.lastname: Diokno
authors.forename: George H
authors.initials: GH
authors.lastname: Miller
authors.forename: Heinz E
authors.initials: HE
authors.lastname: Moser
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004755:Enterobacteriaceae / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011513:Proteus mirabilis / Q000187:drug effects; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D012853:Sisomicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; C550938:plazomicin; D012853:Sisomicin
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