Synthesis, antimicrobial activity, attenuation of aminoglycoside resistance in MRSA, and ribosomal A-site binding of pyrene-neomycin conjugates

Sandra Story; Michael J. Skriba; Krishnagopal Maiti; Ranjan Nihar Ranjan; Natalya N. Degtyareva; Keith D. Green; Verjine Khodaverdian; Adegboyega K. Oyelere; Sylvie Garneau-Tsodikova; Dev P. Arya

doi:10.1016/j.ejmech.2018.11.022

Synthesis, antimicrobial activity, attenuation of aminoglycoside resistance in MRSA, and ribosomal A-site binding of pyrene-neomycin conjugates

Sandra Story, Michael J. Skriba, Krishnagopal Maiti, Ranjan Nihar Ranjan, Natalya N. Degtyareva, Keith D. Green, Verjine Khodaverdian, Adegboyega K. Oyelere, Sylvie Garneau-Tsodikova, Dev P. Arya

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

11 Scopus citations

Abstract

The development of new ligands that have comparable or enhanced therapeutic efficacy relative to current drugs is vital to the health of the global community in the short and long term. One strategy to accomplish this goal is to functionalize sites on current antimicrobials to enhance specificity and affinity while abating resistance mechanisms of infectious organisms. Herein, we report the synthesis of a series of pyrene-neomycin B (PYR-NEO) conjugates, their binding affinity to A-site RNA targets, resistance to aminoglycoside-modifying enzymes (AMEs), and antibacterial activity against a wide variety of bacterial strains of clinical relevance. PYR-NEO conjugation significantly alters the affinities of NEO for bacterial A-site targets. The conjugation of PYR to NEO significantly increased the resistance of NEO to AME modification. PYR-NEO conjugates exhibited broad-spectrum activity towards Gram-positive bacteria, including improved activity against NEO-resistant methicillin-resistant Staphylococcus aureus (MRSA) strains.

Original language	English
Pages (from-to)	381-393
Number of pages	13
Journal	European Journal of Medicinal Chemistry
Volume	163
DOIs	https://doi.org/10.1016/j.ejmech.2018.11.022
State	Published - Feb 1 2019

Bibliographical note

Funding Information:
We thank the National Institute of Health for financial support (grants GM097917, AI111414 to D.P.A.) and (grant AI090048 to S.G.-T.).

Funding Information:
We thank the National Institute of Health for financial support (grants GM097917 , AI111414 to D.P.A.) and (grant AI090048 to S.G.-T.).

Publisher Copyright:
© 2018 Elsevier Masson SAS

Keywords

Aminoglycoside
MRSA
Neomycin
RNA
Ribosome

ASJC Scopus subject areas

Pharmacology
Drug Discovery
Organic Chemistry

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10.1016/j.ejmech.2018.11.022

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Story, S., Skriba, M. J., Maiti, K., Nihar Ranjan, R., Degtyareva, N. N., Green, K. D., Khodaverdian, V., Oyelere, A. K., Garneau-Tsodikova, S., & Arya, D. P. (2019). Synthesis, antimicrobial activity, attenuation of aminoglycoside resistance in MRSA, and ribosomal A-site binding of pyrene-neomycin conjugates. European Journal of Medicinal Chemistry, 163, 381-393. https://doi.org/10.1016/j.ejmech.2018.11.022

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title = "Synthesis, antimicrobial activity, attenuation of aminoglycoside resistance in MRSA, and ribosomal A-site binding of pyrene-neomycin conjugates",

abstract = "The development of new ligands that have comparable or enhanced therapeutic efficacy relative to current drugs is vital to the health of the global community in the short and long term. One strategy to accomplish this goal is to functionalize sites on current antimicrobials to enhance specificity and affinity while abating resistance mechanisms of infectious organisms. Herein, we report the synthesis of a series of pyrene-neomycin B (PYR-NEO) conjugates, their binding affinity to A-site RNA targets, resistance to aminoglycoside-modifying enzymes (AMEs), and antibacterial activity against a wide variety of bacterial strains of clinical relevance. PYR-NEO conjugation significantly alters the affinities of NEO for bacterial A-site targets. The conjugation of PYR to NEO significantly increased the resistance of NEO to AME modification. PYR-NEO conjugates exhibited broad-spectrum activity towards Gram-positive bacteria, including improved activity against NEO-resistant methicillin-resistant Staphylococcus aureus (MRSA) strains.",

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note = "Funding Information: We thank the National Institute of Health for financial support (grants GM097917, AI111414 to D.P.A.) and (grant AI090048 to S.G.-T.). Funding Information: We thank the National Institute of Health for financial support (grants GM097917 , AI111414 to D.P.A.) and (grant AI090048 to S.G.-T.). Publisher Copyright: {\textcopyright} 2018 Elsevier Masson SAS",

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Story, S, Skriba, MJ, Maiti, K, Nihar Ranjan, R, Degtyareva, NN, Green, KD, Khodaverdian, V, Oyelere, AK, Garneau-Tsodikova, S & Arya, DP 2019, 'Synthesis, antimicrobial activity, attenuation of aminoglycoside resistance in MRSA, and ribosomal A-site binding of pyrene-neomycin conjugates', European Journal of Medicinal Chemistry, vol. 163, pp. 381-393. https://doi.org/10.1016/j.ejmech.2018.11.022

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AU - Skriba, Michael J.

AU - Maiti, Krishnagopal

AU - Nihar Ranjan, Ranjan

AU - Degtyareva, Natalya N.

AU - Green, Keith D.

AU - Khodaverdian, Verjine

AU - Oyelere, Adegboyega K.

AU - Garneau-Tsodikova, Sylvie

AU - Arya, Dev P.

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N2 - The development of new ligands that have comparable or enhanced therapeutic efficacy relative to current drugs is vital to the health of the global community in the short and long term. One strategy to accomplish this goal is to functionalize sites on current antimicrobials to enhance specificity and affinity while abating resistance mechanisms of infectious organisms. Herein, we report the synthesis of a series of pyrene-neomycin B (PYR-NEO) conjugates, their binding affinity to A-site RNA targets, resistance to aminoglycoside-modifying enzymes (AMEs), and antibacterial activity against a wide variety of bacterial strains of clinical relevance. PYR-NEO conjugation significantly alters the affinities of NEO for bacterial A-site targets. The conjugation of PYR to NEO significantly increased the resistance of NEO to AME modification. PYR-NEO conjugates exhibited broad-spectrum activity towards Gram-positive bacteria, including improved activity against NEO-resistant methicillin-resistant Staphylococcus aureus (MRSA) strains.

AB - The development of new ligands that have comparable or enhanced therapeutic efficacy relative to current drugs is vital to the health of the global community in the short and long term. One strategy to accomplish this goal is to functionalize sites on current antimicrobials to enhance specificity and affinity while abating resistance mechanisms of infectious organisms. Herein, we report the synthesis of a series of pyrene-neomycin B (PYR-NEO) conjugates, their binding affinity to A-site RNA targets, resistance to aminoglycoside-modifying enzymes (AMEs), and antibacterial activity against a wide variety of bacterial strains of clinical relevance. PYR-NEO conjugation significantly alters the affinities of NEO for bacterial A-site targets. The conjugation of PYR to NEO significantly increased the resistance of NEO to AME modification. PYR-NEO conjugates exhibited broad-spectrum activity towards Gram-positive bacteria, including improved activity against NEO-resistant methicillin-resistant Staphylococcus aureus (MRSA) strains.

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KW - Neomycin

KW - RNA

KW - Ribosome

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ER -

Synthesis, antimicrobial activity, attenuation of aminoglycoside resistance in MRSA, and ribosomal A-site binding of pyrene-neomycin conjugates

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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