1. Int J Mol Sci. 2020 Oct 8;21(19):7411. doi: 10.3390/ijms21197411.

Amphiphilic Aminoglycosides as Medicinal Agents.

Dezanet C(1), Kempf J(1), Mingeot-Leclercq MP(2), Décout JL(1).

Author information:
(1)Molecular Pharmacochemistry Department, University Grenoble Alpes, CNRS, 470 
Rue de la Chimie, F-38000 Grenoble, France.
(2)Cellular and Molecular Pharmacology Unit, Louvain Drug Research Institute, 
Catholic University of Louvain, Avenue E. Mounier 73, UCL B1.73.05, 1200 
Brussels, Belgium.

The conjugation of hydrophobic group(s) to the polycationic hydrophilic core of 
the antibiotic drugs aminoglycosides (AGs), targeting ribosomal RNA, has led to 
the development of amphiphilic aminoglycosides (AAGs). These drugs exhibit 
numerous biological effects, including good antibacterial effects against 
susceptible and multidrug-resistant bacteria due to the targeting of bacterial 
membranes. In the first part of this review, we summarize our work in 
identifying and developing broad-spectrum antibacterial AAGs that constitute a 
new class of antibiotic agents acting on bacterial membranes. The target-shift 
strongly improves antibiotic activity against bacterial strains that are 
resistant to the parent AG drugs and to antibiotic drugs of other classes, and 
renders the emergence of resistant Pseudomonas aeruginosa strains highly 
difficult. Structure-activity and structure-eukaryotic cytotoxicity 
relationships, specificity and barriers that need to be crossed in their 
development as antibacterial agents are delineated, with a focus on their 
targets in membranes, lipopolysaccharides (LPS) and cardiolipin (CL), and the 
corresponding mode of action against Gram-negative bacteria. At the end of the 
first part, we summarize the other recent advances in the field of antibacterial 
AAGs, mainly published since 2016, with an emphasis on the emerging AAGs which 
are made of an AG core conjugated to an adjuvant or an antibiotic drug of 
another class (antibiotic hybrids). In the second part, we briefly illustrate 
other biological and biochemical effects of AAGs, i.e., their antifungal 
activity, their use as delivery vehicles of nucleic acids, of short peptide 
(polyamide) nucleic acids (PNAs) and of drugs, as well as their ability to 
cleave DNA at abasic sites and to inhibit the functioning of connexin 
hemichannels. Finally, we discuss some aspects of structure-activity 
relationships in order to explain and improve the target selectivity of AAGs.

DOI: 10.3390/ijms21197411
PMCID: PMC7583001
PMID: 33049963

Conflict of interest statement: The authors declare no conflict of interest.