Amphiphilic Tobramycin Analogues as Antibacterial and Antifungal Agents

Abstract

In this study, we investigated the in vitro antifungal activities, cytotoxicities, and membrane-disruptive actions of amphiphilic tobramycin (TOB) analogues. The antifungal activities were established by determination of MIC values and in time-kill studies. Cytotoxicity was evaluated in mammalian cell lines. The fungal membrane-disruptive action of these analogues was studied by using the membrane-impermeable dye propidium iodide. TOB analogues bearing a linear alkyl chain at their 6؆-position in a thioether linkage exhibited chain length-dependent antifungal activities. Analogues with C 12 and C 14 chains showed promising antifungal activities against tested fungal strains, with MIC values ranging from 1.95 to 62.5 mg/liter and 1.95 to 7.8 mg/liter, respectively. However, C 4 , C 6 , and C 8 TOB analogues and TOB itself exhibited little to no antifungal activity. Fifty percent inhibitory concentrations (IC 50 s) for the most potent TOB analogues (C 12 and C 14 ) against A549 and Beas 2B cells were 4-to 64-fold and 32-to 64-fold higher, respectively, than their antifungal MIC values against various fungi. Unlike conventional aminoglycoside antibiotics, TOB analogues with alkyl chain lengths of C 12 and C 14 appear to inhibit fungi by inducing apoptosis and disrupting the fungal membrane as a novel mechanism of action. Amphiphilic TOB analogues showed broad-spectrum antifungal activities with minimal mammalian cell cytotoxicity. This study provides novel lead compounds for the development of antifungal drugs.

Synthesis and investigation of novel benzimidazole derivatives as antifungal agents

“…We also observed that all of our bisbenzimidazole derivatives displayed no activity (≥31.2 µg/mL) against A. flavus ATCC MYA-3631 (strain K ). As we and others previously discovered that the addition of long alkyl chains to aminoglycosides such as kanamycin A (KANA), 34 kanamycin B (KANB), 12, 35 and tobramycin (TOB) 11, 13 results in killing of fungal cells through membrane perturbation, we decided to functionalize the bisbenzimidazole core with various alkyl chains hoping for an additive action against fungal growth. The divergent synthetic strategy allowed us to introduce various alkyl chains on either side of the molecule efficiently.…”

“…In recent years, our group has been actively involved in developing novel small molecules as well as aminoglycoside-based antifungal agents to treat both topical and systemic fungal infections. 11–13 Based on a recent report, a high-throughput screening of more than 100,000 individual compounds with heterocyclic cores, in the presence fungal pathogens, led to the identification of a promising benzimidazole scaffold. 14 …”

Tobramycin Variants with Enhanced Ribosome‐Targeting Activity

“…While compounds 3a – j , l , m , p – t , jj , and kk have been described previously, [13–14] compounds 3k , n , o , and u – ii are new. Our collection encompasses a diverse set of 6″-substituents, including linear, branched, and cyclic alkyl groups, and substituted aromatic rings.…”

Synthesis and Biological Activity of Mono- and Di-N-acylated Aminoglycosides

“…In most cases, the overall yields of syntheses are rather low, requiring large quantities of starting materials and many steps to achieve a single product. With the challenges in synthesizing AGs from scratch, several approaches have targeted modifying currently approved AGs including modifications at various positions such as the 1-, 6′-, 21 2″-, 22 5″-, 23 and 6″-positions, 3,24,25 dimerization, 26,27 and covalent attachment to other antibiotics, 23,28 which have all had varying degree of success. Herein, we report on the facile syntheses of AMK, kanamycin A (KAN), netilmicin (NET), sisomicin (SIS), and tobramycin (TOB) mono-and dimodified at the 1-, 6′-, and/or 4‴-amines by glycinyl, carboxybenzyl, and AHB moieties (Scheme 1).…”

“…1 More recently, AGs have also been investigated as potential antifungal agents and as a treatment option for genetic disorders associated with premature termination codons. 2,3 The manifestation of a number of resistance mechanisms that reduce the efficacy of AGs is a major obstacle in the development of novel members of this family of antibiotics. Examples of resistance mechanisms include increased efflux or decreased uptake of AGs by bacterial cells, 4 modifications of the 16S rRNA, 5 and acquisition of AG-modifying enzymes (AMEs) by the bacteria.…”