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.
N1 - Publisher Copyright:
© 2018 Elsevier Masson SAS
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 - http://www.scopus.com/inward/record.url?scp=85057585740&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85057585740&partnerID=8YFLogxK
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 -