Amphiphilic Aminoglycosides as Medicinal Agents

Abstract

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.

An evolutionary conserved detoxification system for membrane lipid–derived peroxyl radicals in Gram-negative bacteria

“…We used 3′,6-dinonyl neamine tetratrifluoroacetate (diNn) as a biological probe to investigate if the loss of BcnA, LcoA, and PsrA results in changes in the amount of anionic phospholipids. diNn is an aminoglycoside derivative that interacts with anionic phospholipids leading to membrane permeabilization and depolarization [ 60 – 63 ]. Compared to the wild-type strain (MIC 75 ± 28 μg ml −1 ), the MIC of diNn was 6- and 3-fold lower in the Δ bcnA (MIC 12.5 μg ml −1 ; p = 0.004) and Δ lcoA (MIC = 26 μg ml −1 ; p = 0.003) mutants, respectively.…”

Aerosol-Mediated Non-Viral Lung Gene Therapy: The Potential of Aminoglycoside-Based Cationic Liposomes

“…The combination of these two lipophosphoramides (which are highly similar structurally, differing only in that the DOPIm headgroup is based on an imidazolium group, whereas DOPI harbors an imidazole group) was previously found to be quite efficient for gene transfection in general [17,51]; this may be due to the protonability of the imidazole group at acidic endosomal pH with a proton sponge effect and an increased fusogenicity. Aminoglycoside-based cationic lipids constitute a class of poly-functional synthetic compounds [52,53] with great potential for gene transfection in vitro as well as in vivo [29,[54][55][56][57]. They were shown to be efficient in the intracellular delivery of siRNA [28], miRNA [58], mRNA [32], and functional proteins [59,60].…”

Interest of Homodialkyl Neamine Derivatives against Resistant P. aeruginosa, E. coli, and β-Lactamases-Producing Bacteria—Effect of Alkyl Chain Length on the Interaction with LPS

“…Neamines bearing two side linear or branched alkyl chains of various length have been identified as potential antibacterial leads [17,21]. To finely delineate the structureactivity relationships relating the antibacterial activity to a lipophilicity window, we synthesized 3 ,6-homodialkyl neamine derivatives with clogP ranging from −13.5 (3 ,6-diheptyl neamine) to −10.3 (3 ,6-diundecyl neamine) with 3 ,6-dioctyl neamine (−12.5), 3 ,6-dinonyl neamine (−11.9), and 3 ,6-didecyl neamine (−11.1) [21].…”

“…In the latter, no linker/tether aimed to be cleaved had been designed. Our group developed a large hemi-synthesis program focusing on amphiphilic aminoglycoside derivatives [17] with the aim to overcome the bottleneck in the development of new antibiotics against P. aeruginosa characterized by a very poor permeability [18]. By adding hydrophobic side chains to the core of conventional aminoglycoside like neamine, it was suspected to increase intrabacterial accumulation and efficiency.…”