Toward overcoming staphylococcus aureus aminoglycoside resistance mechanisms with a functionally designed neomycin analogue

Stephen Hanessian; Alexandre Giguère; Justyna Grzyb; Juan Pablo Maianti; Oscar M. Saavedra; James B. Aggen; Martin S. Linsell; Adam A. Goldblum; Darin J. Hildebrandt; Timothy R. Kane; Paola Dozzo; Micah J. Gliedt; Rowena D. Matias; Lee Ann Feeney; Eliana S. Armstrong

doi:10.1021/ml200202y

Toward overcoming staphylococcus aureus aminoglycoside resistance mechanisms with a functionally designed neomycin analogue

Stephen Hanessian, Alexandre Giguère, Justyna Grzyb, Juan Pablo Maianti, Oscar M. Saavedra, James B. Aggen, Martin S. Linsell, Adam A. Goldblum, Darin J. Hildebrandt, Timothy R. Kane, Paola Dozzo, Micah J. Gliedt, Rowena D. Matias, Lee Ann Feeney, Eliana S. Armstrong

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

Abstract

Deoxygenation of the diol groups in rings A and D of neomycin in combination with the introduction of an N1-(l)-HABA group in the 2-deoxystreptamine subunit (ring B) leads to a novel and potent antibiotic (1) with activity against strains of S. aureus carrying known aminoglycoside resistance determinants, as well as against an extended panel of Methicillin-resistant S. aureus isolates (n = 50). Antibiotic 1 displayed >64 fold improvement in MIC ₅₀ and MIC ₉₀ against this MRSA collection when compared to the clinically relevant aminoglycosides amikacin and gentamicin. The synthesis was achieved in six steps and 15% overall yield.

Original language	English (US)
Pages (from-to)	924-928
Number of pages	5
Journal	ACS Medicinal Chemistry Letters
Volume	2
Issue number	12
DOIs	https://doi.org/10.1021/ml200202y
State	Published - Dec 8 2011
Externally published	Yes

Keywords

Aminoglycoside
MRSA
antibiotics
deoxygenation
enzymatic modification
neomycin analogues
resistance

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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10.1021/ml200202y

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Hanessian, S., Giguère, A., Grzyb, J., Maianti, J. P., Saavedra, O. M., Aggen, J. B., Linsell, M. S., Goldblum, A. A., Hildebrandt, D. J., Kane, T. R., Dozzo, P., Gliedt, M. J., Matias, R. D., Feeney, L. A., & Armstrong, E. S. (2011). Toward overcoming staphylococcus aureus aminoglycoside resistance mechanisms with a functionally designed neomycin analogue. ACS Medicinal Chemistry Letters, 2(12), 924-928. https://doi.org/10.1021/ml200202y

Hanessian, S, Giguère, A, Grzyb, J, Maianti, JP, Saavedra, OM, Aggen, JB, Linsell, MS, Goldblum, AA, Hildebrandt, DJ, Kane, TR, Dozzo, P, Gliedt, MJ, Matias, RD, Feeney, LA & Armstrong, ES 2011, 'Toward overcoming staphylococcus aureus aminoglycoside resistance mechanisms with a functionally designed neomycin analogue', ACS Medicinal Chemistry Letters, vol. 2, no. 12, pp. 924-928. https://doi.org/10.1021/ml200202y

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abstract = "Deoxygenation of the diol groups in rings A and D of neomycin in combination with the introduction of an N1-(l)-HABA group in the 2-deoxystreptamine subunit (ring B) leads to a novel and potent antibiotic (1) with activity against strains of S. aureus carrying known aminoglycoside resistance determinants, as well as against an extended panel of Methicillin-resistant S. aureus isolates (n = 50). Antibiotic 1 displayed >64 fold improvement in MIC 50 and MIC 90 against this MRSA collection when compared to the clinically relevant aminoglycosides amikacin and gentamicin. The synthesis was achieved in six steps and 15% overall yield.",

keywords = "Aminoglycoside, MRSA, antibiotics, deoxygenation, enzymatic modification, neomycin analogues, resistance",

author = "Stephen Hanessian and Alexandre Gigu{\`e}re and Justyna Grzyb and Maianti, {Juan Pablo} and Saavedra, {Oscar M.} and Aggen, {James B.} and Linsell, {Martin S.} and Goldblum, {Adam A.} and Hildebrandt, {Darin J.} and Kane, {Timothy R.} and Paola Dozzo and Gliedt, {Micah J.} and Matias, {Rowena D.} and Feeney, {Lee Ann} and Armstrong, {Eliana S.}",

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AU - Aggen, James B.

AU - Linsell, Martin S.

AU - Goldblum, Adam A.

AU - Hildebrandt, Darin J.

AU - Kane, Timothy R.

AU - Dozzo, Paola

AU - Gliedt, Micah J.

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AB - Deoxygenation of the diol groups in rings A and D of neomycin in combination with the introduction of an N1-(l)-HABA group in the 2-deoxystreptamine subunit (ring B) leads to a novel and potent antibiotic (1) with activity against strains of S. aureus carrying known aminoglycoside resistance determinants, as well as against an extended panel of Methicillin-resistant S. aureus isolates (n = 50). Antibiotic 1 displayed >64 fold improvement in MIC 50 and MIC 90 against this MRSA collection when compared to the clinically relevant aminoglycosides amikacin and gentamicin. The synthesis was achieved in six steps and 15% overall yield.

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KW - MRSA

KW - antibiotics

KW - deoxygenation

KW - enzymatic modification

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KW - resistance

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Toward overcoming staphylococcus aureus aminoglycoside resistance mechanisms with a functionally designed neomycin analogue

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Keywords

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