Mechanisms of resistance to aminoglycoside antibiotics: overview and perspectives
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TLDR
By far the most widespread mechanism of resistance to AGs is the inactivation of these antibiotics by AG-modifying enzymes, and an overview of these mechanisms is provided.Abstract:
Aminoglycoside (AG) antibiotics are used to treat many Gram-negative and some Gram-positive infections and, importantly, multidrug-resistant tuberculosis. Among various bacterial species, resistance to AGs arises through a variety of intrinsic and acquired mechanisms. The bacterial cell wall serves as a natural barrier for small molecules such as AGs and may be further fortified via acquired mutations. Efflux pumps work to expel AGs from bacterial cells, and modifications here too may cause further resistance to AGs. Mutations in the ribosomal target of AGs, while rare, also contribute to resistance. Of growing clinical prominence is resistance caused by ribosome methyltransferases. By far the most widespread mechanism of resistance to AGs is the inactivation of these antibiotics by AG-modifying enzymes. We provide here an overview of these mechanisms by which bacteria become resistant to AGs and discuss their prevalence and potential for clinical relevance.read more
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References
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Revisiting the Nucleotide and Aminoglycoside Substrate Specificity of the Bifunctional Aminoglycoside Acetyltransferase(6')-Ie/Aminoglycoside Phosphotransferase(2")-Ia Enzyme
TL;DR: The data show that the bifunctional enzyme efficiently phosphorylates only 4,6-disubstituted antibiotics; however, phosphorylation does not necessarily result in bacterial resistance, and thus these antibiotics are not substrates.
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Dissecting the cosubstrate structure requirements of the Staphylococcus aureus aminoglycoside resistance enzyme ANT(4
TL;DR: It is demonstrated that the resistance enzyme ANT(4') from Staphylococcus aureus is highly substrate and cosubstrate promiscuous, and it is shown that deoxy-ribonucleotide triphosphates (dNTPs) are better cosubstrates than NTPs.
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Comparative Study of Eis-like Enzymes from Pathogenic and Nonpathogenic Bacteria.
TL;DR: Findings show that this family of acetyltransferase enzymes exists in both mycobacteria and non-mycob bacteria and in both pathogenic and nonpathogenic species, and the bacterial strains described herein should be monitored for rising resistance rates to AGs.
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Influence of Linker Length and Composition on Enzymatic Activity and Ribosomal Binding of Neomycin Dimers
TL;DR: Understanding is advanced of the importance of the linker length and composition for the generation of dimeric aminoglycoside antibiotics capable of avoiding the action of AMEs and selective binding to the bacterial rRNA overbinding to the human rRNA.
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Structure of the bifunctional aminoglycoside-resistance enzyme AAC(6')-Ie-APH(2'')-Ia revealed by crystallographic and small-angle X-ray scattering analysis.
TL;DR: The high-resolution structure of the N-terminal AAC(6')-Ie enzyme is reported as a ternary kanamycin/coenzyme A abortive complex, which supports earlier observations that the presence of the intact α-helix is essential to the activity of both functionalities of the full-length AAC( 6')- Ie-APH(2'')-Ia enzyme.