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. 2010 Nov;54(11):4636-42.
doi: 10.1128/AAC.00572-10. Epub 2010 Aug 30.

Synthesis and spectrum of the neoglycoside ACHN-490

James B Aggen  1 , Eliana S Armstrong, Adam A Goldblum, Paola Dozzo, Martin S Linsell, Micah J Gliedt, Darin J Hildebrandt, Lee Ann Feeney, Aya Kubo, Rowena D Matias, Sara Lopez, Marcela Gomez, Kenneth B Wlasichuk, Raymond Diokno, George H Miller, Heinz E Moser
Affiliations

Synthesis and spectrum of the neoglycoside ACHN-490

James B Aggen et al. Antimicrob Agents Chemother. 2010 Nov.

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.

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Figures

FIG. 1.
FIG. 1.
ACHN-490 structure and AMEs from Gram-negative and Gram-positive (underlined) organisms. AMEs shown with dotted arrows cannot modify ACHN-490.
FIG. 2.
FIG. 2.
Conversion of SIS sulfate to intermediate 2.
FIG. 3.
FIG. 3.
Completion of the synthesis of ACHN-490.
See this image and copyright information in PMC

References

    1. Aggen, J., E. Armstrong, A. Goldblum, P. Dozzo, M. Linsell, M. Gliedt, et al. 2009. Synthesis, structure, and in vitro activity of the neoglycoside ACHN-490, poster F1-840. Abstr. 49th Intersci. Conf. Antimicrob. Agents Chemother. American Society for Microbiology, Washington, DC.
    1. Armstrong, E., D. Biedenbach, R. Jones, and G. Miller. 2009. Surveying aminoglycoside resistance mechanisms: a tool for the development of neoglycosides, poster P-643. Abstr. 19th Eur. Congr. Clin. Microbiol. Infect. Dis. European Society of Clinical Microbiology and Infectious Diseases, Basel, Switzerland.
    1. Biedenbach, D., R. Jones, G. Miller, and E. Armstrong. 2009. Ten-year trend in aminoglycoside resistance from a worldwide collection of gram-negative pathogens (1998-2007), poster P-636. Abstr. 19th Eur. Congr. Clin. Microbiol. Infect. Dis. European Society of Clinical Microbiology and Infectious Diseases, Basel, Switzerland.
    1. Chambers, H. F. 2006. Aminoglycosides, p. 1155-1171. In L. Brunton, J. Lazo, and K. Parker (ed.), Goodman & Gilman's the pharmacological basis of therapeutics, 11th ed. McGraw-Hill, New York, NY.
    1. Clinical and Laboratory Standards Institute. 2009. M100-S19. Performance standards for antimicrobial susceptibility testing; nineteenth informational supplement. Clinical and Laboratory Standards Institute, Wayne, PA.

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