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

Producción científica: Article › revisión exhaustiva

16 Citas (Scopus)

Resumen

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.

Idioma original	English
Páginas (desde-hasta)	381-393
Número de páginas	13
Publicación	European Journal of Medicinal Chemistry
Volumen	163
DOI	https://doi.org/10.1016/j.ejmech.2018.11.022
Estado	Published - feb 1 2019

Nota bibliográfica

Publisher Copyright:
© 2018 Elsevier Masson SAS

Financiación

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

Financiadores	Número del financiador
National Institute of Health National Institute of Minority and Health Disparities Loan Repayment Program
National Institutes of Health (NIH)	AI090048, AI111414
National Institutes of Health (NIH)
National Institute of General Medical Sciences DP2GM119177 Sophie Dumont National Institute of General Medical Sciences	R42GM097917
National Institute of General Medical Sciences DP2GM119177 Sophie Dumont National Institute of General Medical Sciences

ASJC Scopus subject areas

Pharmacology
Drug Discovery
Organic Chemistry

Acceder al documento

10.1016/j.ejmech.2018.11.022

Otros archivos y enlaces

Citar esto

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

@article{140b90acd5c64b7784eadd44fb08b926,

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.",

keywords = "Aminoglycoside, MRSA, Neomycin, RNA, Ribosome",

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

note = "Publisher Copyright: {\textcopyright} 2018 Elsevier Masson SAS",

year = "2019",

month = feb,

day = "1",

doi = "10.1016/j.ejmech.2018.11.022",

language = "English",

volume = "163",

pages = "381--393",

}

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

TY - JOUR

T1 - Synthesis, antimicrobial activity, attenuation of aminoglycoside resistance in MRSA, and ribosomal A-site binding of pyrene-neomycin conjugates

AU - Story, Sandra

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.

PY - 2019/2/1

Y1 - 2019/2/1

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.

KW - Aminoglycoside

KW - MRSA

KW - Neomycin

KW - RNA

KW - Ribosome

UR - https://www.scopus.com/pages/publications/85057585740

UR - https://www.scopus.com/pages/publications/85057585740#tab=citedBy

U2 - 10.1016/j.ejmech.2018.11.022

DO - 10.1016/j.ejmech.2018.11.022

M3 - Article

C2 - 30530174

AN - SCOPUS:85057585740

SN - 0223-5234

VL - 163

SP - 381

EP - 393

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

ER -

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

Resumen

Nota bibliográfica

Financiación

ASJC Scopus subject areas

Acceder al documento

Otros archivos y enlaces

Huella

Citar esto