Neomycin-phenolic conjugates: polycationic amphiphiles with broad-spectrum antibacterial activity, low hemolytic activity and weak serum protein binding

Bioorg Med Chem Lett. 2012 Feb 15;22(4):1499-503. doi: 10.1016/j.bmcl.2012.01.025. Epub 2012 Jan 14.

Abstract

Here we present a proof-of-concept study, combining two known antimicrobial agents into a hybrid structure in order to develop an emergent cationic detergent-like interaction with the bacterial membrane. Six amphiphilic conjugates were prepared by copper (I)-catalyzed 1,3-dipolar cycloaddition between a neomycin B-derived azide and three alkyne-modified phenolic disinfectants. Three conjugates displayed good activity against a variety of clinically relevant Gram positive and Gram negative bacteria, including MRSA, without the high level of hemolysis or strong binding to serum proteins commonly observed with other cationic antimicrobial peptides and detergents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents* / chemistry
  • Anti-Bacterial Agents* / pharmacology
  • Cattle
  • Hemolysis / drug effects
  • Methicillin-Resistant Staphylococcus aureus / drug effects
  • Molecular Structure
  • Neomycin / chemistry*
  • Neomycin / metabolism
  • Neomycin / pharmacology*
  • Phenols / chemistry*
  • Phenols / metabolism
  • Phenols / pharmacology
  • Polyamines / chemistry
  • Polyamines / pharmacology
  • Protein Binding / drug effects
  • Serum Albumin, Bovine / metabolism

Substances

  • Anti-Bacterial Agents
  • Phenols
  • Polyamines
  • polycations
  • Serum Albumin, Bovine
  • Neomycin