Modified Aminoglycosides Bind Nucleic Acids in High-Molecular-Weight Complexes

Ying, Lanqing; Zhu, Hongkun; Fosso, Marina Y.; Fredrick, Kurt

doi:10.3390/antibiotics9020093

Cited by 3 publications

(4 citation statements)

References 32 publications

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“…Collectively, all results suggested that amphiphilic aminoglycosides derived from neamine are interesting molecules for the development, in the future, of new antibiotics targeting bacterial membranes and/or tools for the study of the dynamics of bacterial membranes. How these activities could be extended to antiviral [70] or antifungal [71][72][73] activities and what are the strategies to block LPS biogenesis [74] should also be explored and could open new avenues based on the current work.…”

Section: Discussionmentioning

confidence: 99%

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

Swain

Dezanet

Chalhoub

et al. 2021

IJMS

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Development of novel therapeutics to treat antibiotic-resistant infections, especially those caused by ESKAPE pathogens, is urgent. One of the most critical pathogens is P. aeruginosa, which is able to develop a large number of factors associated with antibiotic resistance, including high level of impermeability. Gram-negative bacteria are protected from the environment by an asymmetric Outer Membrane primarily composed of lipopolysaccharides (LPS) at the outer leaflet and phospholipids in the inner leaflet. Based on a large hemi-synthesis program focusing on amphiphilic aminoglycoside derivatives, we extend the antimicrobial activity of 3′,6-dinonyl neamine and its branched isomer, 3′,6-di(dimethyloctyl) neamine on clinical P. aeruginosa, ESBL, and carbapenemase strains. We also investigated the capacity of 3′,6-homodialkyl neamine derivatives carrying different alkyl chains (C7–C11) to interact with LPS and alter membrane permeability. 3′,6-Dinonyl neamine and its branched isomer, 3′,6-di(dimethyloctyl) neamine showed low MICs on clinical P. aeruginosa, ESBL, and carbapenemase strains with no MIC increase for long-duration incubation. In contrast from what was observed for membrane permeability, length of alkyl chains was critical for the capacity of 3′,6-homodialkyl neamine derivatives to bind to LPS. We demonstrated the high antibacterial potential of the amphiphilic neamine derivatives in the fight against ESKAPE pathogens and pointed out some particular characteristics making the 3′,6-dinonyl- and 3′,6-di(dimethyloctyl)-neamine derivatives the best candidates for further development.

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Section: Discussionmentioning

confidence: 99%

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

Swain

Dezanet

Chalhoub

et al. 2021

IJMS

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“…NEO was found to be the most efficient cleaving AG drug, followed by the AAG 76 (Figure 18) resulting from the conjugation of the NEA core to the nucleic base adenine (EC 50 = 0.09 and 0.15 µM, respectively, and EC 50 (NEA) = 0.9 µM). The study of 6"-substituted variants of TOB, derivatives with C-12 or C-14 linear alkyl substituents, revealed a potent inhibition of reverse transcription in vitro, which was related to nucleic acid binding with high affinity and the formation of high-molecular weight complexes [155]. Stable complex formation was observed with DNA or RNA in single-or double-stranded form, suggesting that the formation of micelles and/or vesicles with surface-bound nucleic acids may be a useful tool to localize nucleic acids to surfaces or deliver nucleic acids to cells or organelles.…”

Section: Some Particular Effects Of Aags On Dna and Rnamentioning

confidence: 99%

Amphiphilic Aminoglycosides as Medicinal Agents

Dezanet

Kempf

Mingeot‐Leclercq

et al. 2020

IJMS

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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.

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“…The chemical modification of already existing antimicrobials has achieved some success, such as the chemical modifications introduced in the β-lactam ring of penicillin to prevent its hydrolysis by penicillinases. Ying et al have synthesized aminoglicosides variants containing different alkyl substituents [7]. The authors report that those variants containing C 12 or C 14 linear alkyl substituents were serendipitously found to strongly inhibit reverse transcriptase.…”

mentioning

confidence: 99%

“…The authors report that those variants containing C 12 or C 14 linear alkyl substituents were serendipitously found to strongly inhibit reverse transcriptase. The authors show evidence that these compounds act by binding nucleic acids with high affinity, forming high-molecular-weight complexes [7]. The compounds were predicted to be useful for nucleic acids localization or in the delivery of nucleic acids to cells or cellular compartments [7].…”

mentioning

confidence: 99%

New Insights into Antibacterial Compounds: From Synthesis and Discovery to Molecular Mechanisms of Action

Leitão

2020

Antibiotics

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The worldwide emergence of microbial resistance to available antibiotics presents a global threat to public health and health systems. This special issue aimed to gather papers describing novel antibiotics, originating form chemical synthesis, repurposing of existent drugs, or from natural sources like plant extracts, herbs and spices. A total of 13 papers were published, covering a wide range of topic, including antimicrobial resistance surveillance studies; synthesis of novel molecules with antimicrobial activities; modification or repurposing of already existing molecules, plant-derived active extracts, and molecules; the effects of antimicrobial therapy on microbiota; and the investigation of novel formulations for human and veterinary uses. After decades of antibiotics discovery decline, antibiotics discovery is boosting. Recent developments of post genomics approaches and bioinformatics tools will most certainly turn the tide in the discovery and development of antimicrobials in this exciting field.

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Modified Aminoglycosides Bind Nucleic Acids in High-Molecular-Weight Complexes

Cited by 3 publications

References 32 publications

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

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

Amphiphilic Aminoglycosides as Medicinal Agents

New Insights into Antibacterial Compounds: From Synthesis and Discovery to Molecular Mechanisms of Action

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