Antifungal Activities of 4″,6″-Disubstituted Amphiphilic Kanamycins

Alfindee, Madher N.; Subedi, Yagya Prasad; Grilley, Michelle; Takemoto, Jon Y.; Chang, Cheng‐Wei Tom

doi:10.3390/molecules24101882

Cited by 8 publications

(8 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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

View full text Add to dashboard Cite

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.

show abstract

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

View full text Add to dashboard Cite

show abstract

“…Such AAGs target bacterial and/or fungal membranes. The identification of non-antibacterial antifungal AAGs targeting fungal membranes demonstrates that the main targets of AAGs can be discriminated [ 121 , 122 , 123 , 124 , 125 , 126 , 127 ]. This selectivity could be found in the difference between monoalkylated and di- or tri-alkylated derivatives of similar lipophilicities.…”

Section: Discussionmentioning

confidence: 99%

“…As an example, the first antifungal non-antibacterial AAGs identified were KAN derivatives. Their development, through the delineation of structure–activity relationships, led to the novel antifungal agent K20 ( Figure 13 ), which is capable of inhibiting many fungal species such as Fusarium graminearum , the causal agent in wheat Fusarium head blight (FHB) [ 122 , 123 , 124 , 125 , 126 , 127 , 128 ]. Plasma membrane permeabilization is probably the principal antifungal mechanism of action of AAGs, leading to the suggestion that they mechanistically and structurally comprise a novel class of antifungal agents [ 121 , 124 , 127 ].…”

Section: Other Biological Activities Of Aagsmentioning

confidence: 99%

See 1 more Smart Citation

Amphiphilic Aminoglycosides as Medicinal Agents

Dezanet

Kempf

Mingeot‐Leclercq

et al. 2020

IJMS

View full text Add to dashboard Cite

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.

show abstract

“…The amphiphilic aminoglycosides particularly kanamycins attracted considerable interest for reviving these old drugs and by structural modifications turning them into antifungal agents [8]. They offer new options for fighting fungal pathogens and are examples of how to confront new therapeutic challenges [8,[22][23][24]. The antibacterial to antifungal conversion of aminoglycosides goes back to the alkyl modification of old drugs, turning them into agrofungicides [25].…”

Section: Discussionmentioning

confidence: 99%

Antifungal Activity of Gentamicin B1 against Systemic Plant Mycoses

Bánfalvi

2020

Molecules

View full text Add to dashboard Cite

Background: Gentamicin is a broad-spectrum aminoglycoside antibiotic produced by Micromonospora purpurea bacteria, effective against Gram-negative bacterial infections. Major fractions of the gentamicin complex (C1, C1a, C2, C2a) possess weak antifungal activity and one of the minor components (A, A1–A4, B, B1, X), gentamicin B1 was found to be a strong antifungal agent. Methods: This work uses in vitro and in vivo dilution methods to compare the antifusarial, antiaspergillic and anticryptococcal effects of gentamicin derivatives and structurally-related congeners. Results: The in vitro antifusarial activity of gentamicin B1 (minimum inhibitory concentration (MIC) 0.4 μg/mL) and structurally-related compounds (MIC 0.8–12.5 μg/mL) suggests that the purpuroseamine ring substituents are responsible for the specific antimycotic effect. The functional groups of the garoseamine and 2-deoxystreptamine rings of gentamicin derivatives are identical in gentamicin compounds and are unlikely to exert a significant antifungal effect. Among soil dermatophytes, Microsporum gypseum was more susceptible to gentamicin B1 (MIC 3.1 µg/mL) than Trichophyton gypseum (MIC 25 µg/mL). The in vitro antifungal effect of gentamicin B1 against plant pathogenic fungi was comparable to primary antifungal agents. Conclusion: Gentamicin is already in medical use. In vitro and preclinical in vivo synergisms of gentamicin B1 with amphotericin B suggest immediate clinical trials starting with subtoxic doses.

show abstract

Antifungal Activities of 4″,6″-Disubstituted Amphiphilic Kanamycins

Cited by 8 publications

References 25 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

Antifungal Activity of Gentamicin B1 against Systemic Plant Mycoses

Contact Info

Product

Resources

About