Aminoglycoside 6′-N-acetyltransferase Type Ib [AAC(6′)-Ib]-Mediated Aminoglycoside Resistance: Phenotypic Conversion to Susceptibility by Silver Ions

Reeves, Craig; Magallón, Jesus; Rocha, Kenneth; Tran, Tung; Phan, Kimberly; Vu, Peter; Yang, Yi; Oakley-Havens, Crista L.; Cedano, José; Jiménez, Verónica; Ramírez, María Soledad; Tolmasky, Marcelo E.

doi:10.3390/antibiotics10010029

Cited by 15 publications

(19 citation statements)

References 51 publications

(81 reference statements)

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“…Following the steps of previous work indicating that selected metal ions interfere with the acetylation reaction [26-29, 31, 43, 44], we tested the effect of Ag 1+ . We chose this ion because, unlike other metals, ionophores were not necessary to observe reversion of resistance in growing bacterial cells when tested as an inhibitor of resistance to aminoglycosides mediated by AAC(6')-Ib [31]. Plazomicin was readily acetylated in vitro in a soluble extract of cells containing a recombinant clone harboring aac(2')-Ia.…”

Section: Discussionmentioning

confidence: 99%

“…These stumbling blocks warrant exploring alternative strategies such as the development of inhibitors of the enzymatic inactivation that together with the aminoglycoside form a combination therapy effective against resistant pathogens [13]. The recent finding that metal ions, some of them in complex with ionophores, inhibit the AAC(6′)-Ib-catalyzed acetylation of aminoglycosides and induce a reduction in the minimal inhibitory concentration (MIC) of amikacin to susceptibility levels proved this concept and increased expectations that multidrug resistant infections could be treated by these combination therapies [26][27][28][29][30][31]. In particular, Ag 1+ inhibits the acetylation of amikacin by AAC(6′)-Ib and reverses resistance in bacteria in culture at low concentrations without needing an ionophore [31].…”

Section: Introductionmentioning

confidence: 99%

“…The recent finding that metal ions, some of them in complex with ionophores, inhibit the AAC(6′)-Ib-catalyzed acetylation of aminoglycosides and induce a reduction in the minimal inhibitory concentration (MIC) of amikacin to susceptibility levels proved this concept and increased expectations that multidrug resistant infections could be treated by these combination therapies [26][27][28][29][30][31]. In particular, Ag 1+ inhibits the acetylation of amikacin by AAC(6′)-Ib and reverses resistance in bacteria in culture at low concentrations without needing an ionophore [31]. This article describes the inhibition of AAC(2′)-Ia-mediated plazomicin-resistance by Ag 1+ in Escherichia coli harboring a recombinant clone containing the aac(2′)-Ia gene.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of Enzymatic Acetylation-Mediated Resistance to Plazomicin by Silver Ions

Ngo¹,

Magaña²,

Tran³

et al. 2023

Preprint

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Plazomicin is a recently 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′-N-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 acetylation of numerous aminoglycosides catalyzed by the aminoglycoside 6′-N-acetyltransferase type Ib [AAC(6′)-Ib]. In particular, Ag1+, 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 Escherichia coli carrying aac(2′)-Ia. The resistance reversion assays produced equivalent results when the structural gene was expressed under the control of the natural or the blaTEM-1 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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inhibition of Enzymatic Acetylation-Mediated Resistance to Plazomicin by Silver Ions

Ngo¹,

Magaña²,

Tran³

et al. 2023

Preprint

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show abstract

“…Amikacin is an aminoglycoside most commonly administered intravenously and intramuscularly, yet other routes are also utilized, such as intrathecal, intraventricular, topical, and inhaled 8 , 17 , 18 . In our quest to identify compounds that inhibit the AAC(6′)-Ib amikacin-disabling action, we recently found that various cations effectively interfere with the enzymatic inactivation 11 , 12 , 19 – 21 . In the case of Zn 2+ , the concentrations needed to inhibit growth of amikacin-resistant cells in the presence of the antibiotic are significantly reduced if the cation is added to the growth media in complex with ionophores 11 – 13 , 20 – 22 .…”

Section: Discussionmentioning

confidence: 99%

Amikacin potentiator activity of zinc complexed to a pyrithione derivative with enhanced solubility

Magallón

Reeves

et al. 2022

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Resistance to amikacin in Gram-negatives is usually mediated by the 6'-N-acetyltransferase type Ib [AAC(6')-Ib], which catalyzes the transfer of an acetyl group from acetyl CoA to the 6' position of the antibiotic molecule. A path to continue the effective use of amikacin against resistant infections is to combine it with inhibitors of the inactivating reaction. We have recently observed that addition of Zn2+ to in-vitro enzymatic reactions, obliterates acetylation of the acceptor antibiotic. Furthermore, when added to amikacin-containing culture medium in complex to ionophores such as pyrithione (ZnPT), it prevents the growth of resistant strains. An undesired property of ZnPT is its poor water-solubility, a problem that currently affects a large percentage of newly designed drugs. Water-solubility helps drugs to dissolve in body fluids and be transported to the target location. We tested a pyrithione derivative described previously (Magda et al. Cancer Res 68:5318–5325, 2008) that contains the amphoteric group di(ethyleneglycol)-methyl ether at position 5 (compound 5002), a modification that enhances the solubility. Compound 5002 in complex with zinc (Zn5002) was tested to assess growth inhibition of amikacin-resistant Acinetobacter baumannii and Klebsiella pneumoniae strains in the presence of the antibiotic. Zn5002 complexes in combination with amikacin at different concentrations completely inhibited growth of the tested strains. However, the concentrations needed to achieve growth inhibition were higher than those required to achieve the same results using ZnPT. Time-kill assays showed that the effect of the combination amikacin/Zn5002 was bactericidal. These results indicate that derivatives of pyrithione with enhanced water-solubility, a property that would make them drugs with better bioavailability and absorption, are a viable option for designing inhibitors of the resistance to amikacin mediated by AAC(6')-Ib, an enzyme commonly found in the clinics.

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“…Amikacin is an aminoglycoside most commonly administered intravenously and intramuscularly, yet other routes are also utilized, such as intrathecal, intraventricular, topical, and inhaled 8,17,18 . In our quest to identify compounds that inhibit the AAC(6′)-Ib amikacin-disabling action, we recently found that various cations effectively interfere with the enzymatic inactivation 11,12,[19][20][21] . In the case of Zn 2+ , the concentrations needed to inhibit growth of amikacin-resistant cells in the presence of the antibiotic are significantly reduced if the cation is added to the growth media in complex with ionophores [11][12][13][20][21][22] .…”

Section: Discussionmentioning

confidence: 99%

Amikacin potentiator activity of zinc complexed to a pyrithione derivative with enhanced solubility

Magallón

Reeves

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

Resistance to amikacin in Gram-negatives is usually mediated by the 6'-N-acetyltransferase type Ib [AAC(6')-Ib], which catalyzes the transfer of an acetyl group from acetyl CoA to the 6' position of the antibiotic molecule. A path to continue the effective use of amikacin against resistant infections is to combine it with inhibitors of the inactivating reaction. We have recently observed that addition of Zn2+ to in-vitro enzymatic reactions, obliterates acetylation of the acceptor antibiotic. Furthermore, when added to amikacin-containing culture medium in complex to ionophores such as pyrithione (ZnPT), it prevents the growth of resistant strains. An undesired property of ZnPT is its poor water-solubility, a problem that currently affects a large percentage of newly designed drugs. Water-solubility helps drugs to dissolve in body fluids and be transported to the target location. We tested a pyrithione derivative described previously (Magda et al. Cancer Res. 2008, 68:5318-5325) that contains the amphoteric group di(ethyleneglycol)-methyl ether at position 5 (compound 5002), a modification that enhances the solubility. Compound 5002 in complex with zinc (Zn5002) was tested to assess growth inhibition of amikacin-resistant Acinetobacter baumannii and Klebsiella pneumoniae strains in the presence of the antibiotic. Zn5002 complexes in combination with amikacin at different concentrations completely inhibited growth of the tested strains. However, the concentrations needed to achieve growth inhibition were higher than those required to achieve the same results using ZnPT. Time-kill assays showed that the effect of the combination amikacin/Zn5002 was bactericidal. These results indicate that derivatives of pyrithione with enhanced water-solubility, a property that would make them drugs with better bioavailability and absorption, are a viable option for designing inhibitors of the resistance to amikacin mediated by AAC(6')-Ib, an enzyme commonly found in the clinics.

show abstract

Aminoglycoside 6′-N-acetyltransferase Type Ib [AAC(6′)-Ib]-Mediated Aminoglycoside Resistance: Phenotypic Conversion to Susceptibility by Silver Ions

Cited by 15 publications

References 51 publications

Inhibition of Enzymatic Acetylation-Mediated Resistance to Plazomicin by Silver Ions

Inhibition of Enzymatic Acetylation-Mediated Resistance to Plazomicin by Silver Ions

Amikacin potentiator activity of zinc complexed to a pyrithione derivative with enhanced solubility

Amikacin potentiator activity of zinc complexed to a pyrithione derivative with enhanced solubility

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