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Recent Development on the New Applications of Aminoglycosides

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Bioorganic Chemistry".

Deadline for manuscript submissions: closed (30 November 2018) | Viewed by 44245

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Special Issue Editor

Prof. Dr. Cheng-Wei Tom Chang

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Guest Editor

Department of Chemistry and Biochemistry, Utah State University, 0300 Old Main Hill, Logan, UT 84322-0300, USA
Interests: aminoglycosides; antibacterial; antifungal; antimicrobial; anticancer; anti-imflammatory; biomass conversion and utilization
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Ever since the discovery of aminoglycoside antibiotics, mainstream research in aminoglycoside has often focused on chemical and biological studies of their antibacterial activity, mechanisms of bacterial resistance, and structural analyses that are also related to antibacterial activity or bacterial resistance. However, there have been several significant and novel results in aminoglycoside research, generated beyond traditional scopes of aminoglycosides. The proposed Special Issue will provide a platform for researchers to publicize their latest achievements and perspectives in aminoglycoside research. The topics may include, but are not limited to, the following areas:

Amphiphilic aminoglycosides as new class of antibacterial agent
Amphiphilic aminoglycosides as new class of antifungal agent
New diagnostic techniques (fluorescence, mass spec, cell-based, etc.) using aminoglycosides
Latest results from the biosynthesis and chemical synthesis of aminoglycoside
Using aminoglycosides as potential treatment of human genetic diseases

In summary, this Special Issue will cover reviews or research advances in recent aminoglycoside research. In addition to the traditional antibacterial research, new applications and multidisciplinary approaches will be the important features for this Special Issue.

Prof. Tom Chang
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

aminoglycosides
antibacterial
antifungal
antimicrobial
protein inhibition
disease diagnostic or detection

Published Papers (5 papers)

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Research

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12 pages, 4078 KiB

Open AccessArticle

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

by Madher N. Alfindee, Yagya P. Subedi, Michelle M. Grilley, Jon Y. Takemoto and Cheng-Wei T. Chang

Molecules 2019, 24(10), 1882; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules24101882 - 16 May 2019

Cited by 8 | Viewed by 3037

Abstract

Amphiphilic kanamycins derived from the classic antibiotic kanamycin have attracted interest due to their novel bioactivities beyond inhibition of bacteria. In this study, the recently described 4″,6″-diaryl amphiphilic kanamycins reported as inhibitors of connexin were examined for their antifungal activities. Nearly all 4″,6″-diaryl amphiphilic kanamycins tested had antifungal activities comparable to those of 4″,6″-dialkyl amphiphilic kanamycins, reported previously against several fungal strains. The minimal growth inhibitory concentrations (MICs) correlated with the degree of amphiphilicity (cLogD) of the di-substituted amphiphilic kanamycins. Using the fluorogenic dyes, SYTOX^TM Green and propidium iodide, the most active compounds at the corresponding MICs or at 2×MICs caused biphasic dye fluorescence increases over time with intact cells. Further lowering the concentrations to half MICs caused first-order dye fluorescence increases. Interestingly, 4×MIC or 8×MIC levels resulted in fluorescence suppression that did not correlate with the MIC and plasma membrane permeabilization. The results show that 4″,6″-diaryl amphiphilic kanamycins are antifungal and that amphiphilicity parameter cLogD is useful for the design of the most membrane-active versions. A cautionary limitation of fluorescence suppression was revealed when using fluorogenic dyes to measure cell-permeation mechanisms with these antifungals at high concentrations. Finally, 4″,6″-diaryl amphiphilic kanamycins elevate the production of cellular reactive oxygen species as other reported amphiphilic kanamycins. Full article

(This article belongs to the Special Issue Recent Development on the New Applications of Aminoglycosides)

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23 pages, 3214 KiB

Open AccessFeature PaperArticle

Differential Effects of Linkers on the Activity of Amphiphilic Tobramycin Antifungals

by Marina Y. Fosso, Sanjib K. Shrestha, Nishad Thamban Chandrika, Emily K. Dennis, Keith D. Green and Sylvie Garneau-Tsodikova

Molecules 2018, 23(4), 899; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules23040899 - 13 Apr 2018

Cited by 11 | Viewed by 3844

Abstract

As the threat associated with fungal infections continues to rise and the availability of antifungal drugs remains a concern, it becomes obvious that the need to bolster the antifungal armamentarium is urgent. Building from our previous findings of tobramycin (TOB) derivatives with antifungal activity, we further investigate the effects of various linkers on the biological activity of these aminoglycosides. Herein, we analyze how thioether, sulfone, triazole, amide, and ether functionalities affect the antifungal activity of alkylated TOB derivatives against 22 Candida, Cryptococcus, and Aspergillus species. We also evaluate their impact on the hemolysis of murine erythrocytes and the cytotoxicity against mammalian cell lines. While the triazole linker appears to confer optimal activity overall, all of the linkers incorporated into the TOB derivatives resulted in compounds that are very effective against the Cryptococcus neoformans species, with MIC values ranging from 0.48 to 3.9 μg/mL. Full article

(This article belongs to the Special Issue Recent Development on the New Applications of Aminoglycosides)

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5178 KiB

Open AccessArticle

Inhibition by Commercial Aminoglycosides of Human Connexin Hemichannels Expressed in Bacteria

by Mariana C. Fiori, Srinivasan Krishnan, Abbey Kjellgren, Luis G. Cuello and Guillermo A. Altenberg

Molecules 2017, 22(12), 2063; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules22122063 - 25 Nov 2017

Cited by 11 | Viewed by 6310

Abstract

In addition to gap junctional channels that mediate cell-to-cell communication, connexins form hemichannels that are present at the plasma membrane. Since hemichannels are permeable to small hydrophilic compounds, including metabolites and signaling molecules, their abnormal opening can cause or contribute to cell damage in disorders such as cardiac infarct, stroke, deafness, skin diseases, and cataracts. Therefore, hemichannels are potential pharmacological targets. A few aminoglycosides, well-known broad-spectrum antibiotics, have been shown to inhibit hemichannels. Here, we tested several commercially available aminoglycosides for inhibition of human connexin hemichannels using a cell-based bacterial growth complementation assay that we developed recently. We found that kanamycin A, kanamycin B, geneticin, neomycin, and paromomycin are effective inhibitors of hemichannels formed by connexins 26, 43, and 46 (Cx26, Cx43, and Cx46). Because of the >70 years of clinical experience with aminoglycosides and the fact that several of the aminoglycosides tested here have been used in humans, they are promising starting points for the development of effective connexin hemichannel inhibitors. Full article

(This article belongs to the Special Issue Recent Development on the New Applications of Aminoglycosides)

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Review

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18 pages, 2929 KiB

Open AccessFeature PaperReview

Overcoming Aminoglycoside Enzymatic Resistance: Design of Novel Antibiotics and Inhibitors

by Sandra G. Zárate, M. Luisa De la Cruz Claure, Raúl Benito-Arenas, Julia Revuelta, Andrés G. Santana and Agatha Bastida

Molecules 2018, 23(2), 284; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules23020284 - 30 Jan 2018

Cited by 57 | Viewed by 12475

Abstract

Resistance to aminoglycoside antibiotics has had a profound impact on clinical practice. Despite their powerful bactericidal activity, aminoglycosides were one of the first groups of antibiotics to meet the challenge of resistance. The most prevalent source of clinically relevant resistance against these therapeutics is conferred by the enzymatic modification of the antibiotic. Therefore, a deeper knowledge of the aminoglycoside-modifying enzymes and their interactions with the antibiotics and solvent is of paramount importance in order to facilitate the design of more effective and potent inhibitors and/or novel semisynthetic aminoglycosides that are not susceptible to modifying enzymes. Full article

(This article belongs to the Special Issue Recent Development on the New Applications of Aminoglycosides)

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2440 KiB

Open AccessReview

Amikacin: Uses, Resistance, and Prospects for Inhibition

by Maria S. Ramirez and Marcelo E. Tolmasky

Molecules 2017, 22(12), 2267; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules22122267 - 19 Dec 2017

Cited by 138 | Viewed by 17711

Abstract

Aminoglycosides are a group of antibiotics used since the 1940s to primarily treat a broad spectrum of bacterial infections. The primary resistance mechanism against these antibiotics is enzymatic modification by aminoglycoside-modifying enzymes that are divided into acetyl-transferases, phosphotransferases, and nucleotidyltransferases. To overcome this problem, new semisynthetic aminoglycosides were developed in the 70s. The most widely used semisynthetic aminoglycoside is amikacin, which is refractory to most aminoglycoside modifying enzymes. Amikacin was synthesized by acylation with the l-(−)-γ-amino-α-hydroxybutyryl side chain at the C-1 amino group of the deoxystreptamine moiety of kanamycin A. The main amikacin resistance mechanism found in the clinics is acetylation by the aminoglycoside 6′-N-acetyltransferase type Ib [AAC(6′)-Ib], an enzyme coded for by a gene found in integrons, transposons, plasmids, and chromosomes of Gram-negative bacteria. Numerous efforts are focused on finding strategies to neutralize the action of AAC(6′)-Ib and extend the useful life of amikacin. Small molecules as well as complexes ionophore-Zn⁺² or Cu⁺² were found to inhibit the acetylation reaction and induced phenotypic conversion to susceptibility in bacteria harboring the aac(6′)-Ib gene. A new semisynthetic aminoglycoside, plazomicin, is in advance stage of development and will contribute to renewed interest in this kind of antibiotics. Full article

(This article belongs to the Special Issue Recent Development on the New Applications of Aminoglycosides)

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