2. Academic Validation
  3. Synthesis, antimicrobial activity, attenuation of aminoglycoside resistance in MRSA, and ribosomal A-site binding of pyrene-neomycin conjugates

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

  • Eur J Med Chem. 2019 Feb 1:163:381-393. doi: 10.1016/j.ejmech.2018.11.022.
Sandra Story 1,  Michael J Skriba 2,  Krishnagopal Maiti 2,  Nihar Ranjan 3,  Natalya N Degtyareva 1,  Keith D Green 4,  Verjine Khodaverdian 5,  Adegboyega K Oyelere 6,  Sylvie Garneau-Tsodikova 4,  Dev P Arya 7
Affiliations

Affiliations

  • 1 NUBAD, LLC, Greenville, SC, 29605, United States.
  • 2 Department of Chemistry, Clemson University, Clemson, SC, 29634, United States.
  • 3 Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Raebareli, 229010, India.
  • 4 College of Pharmacy, University of Kentucky, Lexington, KY, 40536-0596, United States.
  • 5 School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA, 30332-0400, United States.
  • 6 School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA, 30332-0400, United States; Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, 30332, United States.
  • 7 NUBAD, LLC, Greenville, SC, 29605, United States; Department of Chemistry, Clemson University, Clemson, SC, 29634, United States. Electronic address: [email protected].
PMID: 30530174 DOI: 10.1016/j.ejmech.2018.11.022
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.

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