Inhibition of Enzymatic Acetylation-Mediated Resistance to Plazomicin by Silver Ions
Plazomicin is a recent U.S. Food and Drug Administration (FDA)-approved semisynthetic aminoglycoside. Its structure consists of a sisomicin scaffold modified by adding a 2(S)-hydroxy aminobutyryl group at the N1 position and a hydroxyethyl substituent at the 6′ position. These substitutions produced...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-02-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/16/2/236 |
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| author | David Ngo Angel J. Magaña Tung Tran Jan Sklenicka Kimberly Phan Brian Eykholt Verónica Jimenez María S. Ramirez Marcelo E. Tolmasky |
| author_facet | David Ngo Angel J. Magaña Tung Tran Jan Sklenicka Kimberly Phan Brian Eykholt Verónica Jimenez María S. Ramirez Marcelo E. Tolmasky |
| author_sort | David Ngo |
| collection | DOAJ |
| description | Plazomicin is a recent U.S. Food and Drug Administration (FDA)-approved semisynthetic aminoglycoside. Its structure consists of a sisomicin scaffold modified by adding a 2(S)-hydroxy aminobutyryl group at the N1 position and a hydroxyethyl substituent at the 6′ position. These substitutions produced a molecule refractory to most aminoglycoside-modifying enzymes. The main enzyme within this group that recognizes plazomicin as substrate is the aminoglycoside 2′-<i>N</i>-acetyltransferase type Ia [AAC(2′)-Ia], which reduces the antibiotic’s potency. Designing formulations that combine an antimicrobial with an inhibitor of resistance is a recognized strategy to extend the useful life of existing antibiotics. We have recently found that several metal ions inhibit the enzymatic inactivation of numerous aminoglycosides mediated by the aminoglycoside 6′-<i>N</i>-acetyltransferase type Ib [AAC(6′)-Ib]. In particular, Ag<sup>+</sup>, which also enhances the effect of aminoglycosides by other mechanisms, is very effective in interfering with AAC(6′)-Ib-mediated resistance to amikacin. Here we report that silver acetate is a potent inhibitor of AAC(2′)-Ia-mediated acetylation of plazomicin in vitro, and it reduces resistance levels of <i>Escherichia coli</i> carrying <i>aac(2′)-Ia</i>. The resistance reversion assays produced equivalent results when the structural gene was expressed under the control of the natural or the <i>bla</i><sub>TEM-1</sub> promoters. The antibiotic effect of plazomicin in combination with silver was bactericidal, and the mix did not show significant toxicity to human embryonic kidney 293 (HEK293) cells. |
| first_indexed | 2024-03-11T08:18:05Z |
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| id | doaj.art-8f5558aee32c47369259aa92ccc552b2 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-11T08:18:05Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-8f5558aee32c47369259aa92ccc552b22023-11-16T22:36:53ZengMDPI AGPharmaceuticals1424-82472023-02-0116223610.3390/ph16020236Inhibition of Enzymatic Acetylation-Mediated Resistance to Plazomicin by Silver IonsDavid Ngo0Angel J. Magaña1Tung Tran2Jan Sklenicka3Kimberly Phan4Brian Eykholt5Verónica Jimenez6María S. Ramirez7Marcelo E. Tolmasky8Center for Applied Biotechnology Studies, Department of Biological Science, California State University Fullerton, Fullerton, CA 92831, USACenter for Applied Biotechnology Studies, Department of Biological Science, California State University Fullerton, Fullerton, CA 92831, USACenter for Applied Biotechnology Studies, Department of Biological Science, California State University Fullerton, Fullerton, CA 92831, USACenter for Applied Biotechnology Studies, Department of Biological Science, California State University Fullerton, Fullerton, CA 92831, USACenter for Applied Biotechnology Studies, Department of Biological Science, California State University Fullerton, Fullerton, CA 92831, USACenter for Applied Biotechnology Studies, Department of Biological Science, California State University Fullerton, Fullerton, CA 92831, USACenter for Applied Biotechnology Studies, Department of Biological Science, California State University Fullerton, Fullerton, CA 92831, USACenter for Applied Biotechnology Studies, Department of Biological Science, California State University Fullerton, Fullerton, CA 92831, USACenter for Applied Biotechnology Studies, Department of Biological Science, California State University Fullerton, Fullerton, CA 92831, USAPlazomicin is a recent U.S. Food and Drug Administration (FDA)-approved semisynthetic aminoglycoside. Its structure consists of a sisomicin scaffold modified by adding a 2(S)-hydroxy aminobutyryl group at the N1 position and a hydroxyethyl substituent at the 6′ position. These substitutions produced a molecule refractory to most aminoglycoside-modifying enzymes. The main enzyme within this group that recognizes plazomicin as substrate is the aminoglycoside 2′-<i>N</i>-acetyltransferase type Ia [AAC(2′)-Ia], which reduces the antibiotic’s potency. Designing formulations that combine an antimicrobial with an inhibitor of resistance is a recognized strategy to extend the useful life of existing antibiotics. We have recently found that several metal ions inhibit the enzymatic inactivation of numerous aminoglycosides mediated by the aminoglycoside 6′-<i>N</i>-acetyltransferase type Ib [AAC(6′)-Ib]. In particular, Ag<sup>+</sup>, which also enhances the effect of aminoglycosides by other mechanisms, is very effective in interfering with AAC(6′)-Ib-mediated resistance to amikacin. Here we report that silver acetate is a potent inhibitor of AAC(2′)-Ia-mediated acetylation of plazomicin in vitro, and it reduces resistance levels of <i>Escherichia coli</i> carrying <i>aac(2′)-Ia</i>. The resistance reversion assays produced equivalent results when the structural gene was expressed under the control of the natural or the <i>bla</i><sub>TEM-1</sub> promoters. The antibiotic effect of plazomicin in combination with silver was bactericidal, and the mix did not show significant toxicity to human embryonic kidney 293 (HEK293) cells.https://www.mdpi.com/1424-8247/16/2/236AAC(2′)-Iaaminoglycoside 2′-<i>N</i>-acetyltransferase type Iaaminoglycosidemultidrug resistancemetal ionsplazomicin |
| spellingShingle | David Ngo Angel J. Magaña Tung Tran Jan Sklenicka Kimberly Phan Brian Eykholt Verónica Jimenez María S. Ramirez Marcelo E. Tolmasky Inhibition of Enzymatic Acetylation-Mediated Resistance to Plazomicin by Silver Ions Pharmaceuticals AAC(2′)-Ia aminoglycoside 2′-<i>N</i>-acetyltransferase type Ia aminoglycoside multidrug resistance metal ions plazomicin |
| title | Inhibition of Enzymatic Acetylation-Mediated Resistance to Plazomicin by Silver Ions |
| title_full | Inhibition of Enzymatic Acetylation-Mediated Resistance to Plazomicin by Silver Ions |
| title_fullStr | Inhibition of Enzymatic Acetylation-Mediated Resistance to Plazomicin by Silver Ions |
| title_full_unstemmed | Inhibition of Enzymatic Acetylation-Mediated Resistance to Plazomicin by Silver Ions |
| title_short | Inhibition of Enzymatic Acetylation-Mediated Resistance to Plazomicin by Silver Ions |
| title_sort | inhibition of enzymatic acetylation mediated resistance to plazomicin by silver ions |
| topic | AAC(2′)-Ia aminoglycoside 2′-<i>N</i>-acetyltransferase type Ia aminoglycoside multidrug resistance metal ions plazomicin |
| url | https://www.mdpi.com/1424-8247/16/2/236 |
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