Aminoglycosides: Mechanisms of Action and Resistance

Serio, Alisa W.; Magalhães, Maria L.B.; Blanchard, John S.; Connolly, Lynn

doi:10.1007/978-3-319-46718-4_14

Cited by 25 publications

(34 citation statements)

References 165 publications

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“…Aminoglycosides are a group of antibiotics primarily used to treat a wide spectrum of bacterial infections [ 1 , 2 , 3 , 4 ]. However, modern medicine has found other uses for these agents that include treatments for various genetic disorders and Meniere’s disease [ 5 , 6 , 7 , 8 ].…”

Section: A Brief History Of Aminoglycoside Antibioticsmentioning

confidence: 99%

Amikacin: Uses, Resistance, and Prospects for Inhibition

2017

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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.

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Section: A Brief History Of Aminoglycoside Antibioticsmentioning

confidence: 99%

Amikacin: Uses, Resistance, and Prospects for Inhibition

2017

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“…In contrast, the investigation of Mokhtari et al [17] reported lower resistance rates to gentamicin and amikacin. The ability of K. pneumoniae to produce a wide variety of AMEs confers high resistance against aminoglycosides, in addition to overexpression of efflux pumps and loss of porins from cell membrane [4,6]. The emergence of 16S rRNA methylases provides high resistance to all common aminoglycosides [4].…”

Section: Resultsmentioning

confidence: 99%

“…Aminoglycosides and fluoroquinolones become among the last antimicrobial options used to treat infections with K. pneumoniae. Aminoglycosides act by binding to the highly conserved A site, a part of the 16S rRNA within the small subunit 30S of bacterial ribosome, leading to the blockage of protein synthesis [4]. On the other hand, fluoroquinolones act by preventing the synthesis and replication of the bacterial DNA by targeting topoisomerases (DNA gyrase and topoisomerase IV) [5].…”

Section: Introductionmentioning

confidence: 99%

“…Three families of the AMEs were detected in K. pneumoniae, including aminoglycosides acetyltransferases (AACs), aminoglycosides phosphotransferases (APHs), and aminoglycosides nucleotidyltransferases (ANTs). These are known to inhibit the active role of aminoglycosides by N-acetylation, O-phosphorylation, and Onucleotidylation of the aforementioned drugs, respectively [4,6]. Interestingly, the frequency of mutations in the AMEs-encoding genes increases the diversity of these genes through the contribution in the emergence of new alleles.…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, the frequency of mutations in the AMEs-encoding genes increases the diversity of these genes through the contribution in the emergence of new alleles. This results in reducing the active role of common used aminoglycosides which imposes a great health challenge for both patients and physicians that can be inevitably difficult to be confronted and controlled [4,6].…”

Section: Introductionmentioning

confidence: 99%

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Investigation for some Aminoglycosides Modifying Enzymes- Encoding Genes and Co-Resistance to Fluoroquinolones among Klebsiella pneumoniae Isolates from Different Clinical Cases

Mustafa

Abdullah

2020

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In this study, we investigated the prevalence of aminoglycosides modifying enzymes (AMEs)-encoding genes, including aac(3′)-ΙΙ, ant(3′′)-Ι, aph(3′)-VΙ, and aac(6′)-Ιb-cr and their potential effect on the development of resistance to aminoglycosides and fluoroquinolones in clinical isolates of Klebsiella pneumoniae. According to the phenotypic and biochemical characteristics of 150 clinical samples, 50 (33%) isolates were identified as K. pneumoniae. These isolates were collected from different clinical sources, including urine (15, 30%), blood (12, 24%), sputum (9, 18%), wounds (9, 18%), and burns (5, 10%). The minimum inhibitory concentrations (MICs) assay revealed that the resistance values of isolates were 25 (50%) to gentamicin (≥16µg/ml), 21 (42%) to amikacin (≥64 µg/ml), 15 (30%) to ciprofloxacin (≥4 µg/ml), and 11 (22%) to levofloxacin (≥8 µg/ml). Genotypic detection revealed that aac(3′)-ΙΙ, aac(6′)-Ιb-cr, aph(3′)-VΙ, and ant(3′′)-Ι were found in 47 (94%), 38 (76%), 18 (36%), and 8 (16%) of K. pneumoniae isolates, respectively. The co-resistance pattern for both aminoglycosides and fluoroquinolones was detected in 14 (28%) isolates, of these 10 (71.4%) harbored aac(6′)-Ιb-cr. DNA sequencing for some isolates revealed the presence of point and frameshift mutations in the studied genes. Our study findings suggest that the presence of missense and frameshift mutations may contribute to the elevated resistance to amikacin and gentamicin. The increased prevalence of AMEs-encoding genes among K. pneumoniae isolates could contribute in reducing susceptibility to amikacin and gentamicin. The co-resistance pattern for aminoglycosides and fluoroquinolones was highly associated with the presence of the aac(6′)-Ιb-cr gene.

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