Synthesis and spectrum of the neoglycoside ACHN-490.
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.
Aggen
James B
JB
Achaogen, Inc., 7000 Shoreline Court, South San Francisco, CA 94080, USA.
Armstrong
Eliana S
ES
Goldblum
Adam A
AA
Dozzo
Paola
P
Linsell
Martin S
MS
Gliedt
Micah J
MJ
Hildebrandt
Darin J
DJ
Feeney
Lee Ann
LA
Kubo
Aya
A
Matias
Rowena D
RD
Lopez
Sara
S
Gomez
Marcela
M
Wlasichuk
Kenneth B
KB
Diokno
Raymond
R
Miller
George H
GH
Moser
Heinz E
HE
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
D000900:Anti-Bacterial Agents; C550938:plazomicin; D012853:Sisomicin
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