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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Biochemical and Structural Analysis of an Eis Family Aminoglycoside Acetyltransferase from Bacillus anthracis.
Keith D. Green,Tapan Biswas,Changsoo Chang,Ruiying Wu,Wei Chen,Brian K. Janes,Dominika Chalupska,Piotr Gornicki,Philip C. Hanna,Oleg V. Tsodikov,Andrzej Joachimiak,Sylvie Garneau-Tsodikova +11 more
TL;DR: The results suggest that acetyltransferases of the Eis family evolved divergently to garner distinct specificities while conserving catalytic efficiency, possibly to counter distinct chemical challenges.
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Review: The Molecular Basis of Resistance in Mycobaterium tuberculosis
TL;DR: A molecular understanding of the series of events that render M. tuberculosis multi-drug resistant is very important in order to find a fast and appropriated diagnosis as well as a new target for new drugs.
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Toxicity modulation, resistance enzyme evasion, and A-site X-ray structure of broad-spectrum antibacterial neomycin analogs.
Juan Pablo Maianti,Hiroki Kanazawa,Paola Dozzo,Rowena D. Matias,Lee Ann Feeney,Eliana Saxon Armstrong,Darin Hildebrandt,Timothy R. Kane,Micah J. Gliedt,Adam Aaron Goldblum,Martin S. Linsell,James B. Aggen,Jiro Kondo,Stephen Hanessian +13 more
TL;DR: Cytotoxicity in kidney-derived cells was significantly reduced for the derivative featuring the novel β,β-difluoro-HABA group, which masks one net charge by lowering the pKa without compromising antibacterial potency.
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A Structural Basis for the Antibiotic Resistance Conferred by an A1408G Mutation in 16S rRNA and for the Antiprotozoal Activity of Aminoglycosides
TL;DR: These structures show how bacteria acquire high-level resistance against aminoglycosides by the mutation A1408G.
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Small-Angle X-Ray Scattering Analysis of the Bifunctional Antibiotic Resistance Enzyme Aminoglycoside (6′) Acetyltransferase-Ie/Aminoglycoside (2″) Phosphotransferase-Ia Reveals a Rigid Solution Structure
TL;DR: It is proposed that the rigid structure contributes to improved electrostatic steering of aminoglycoside substrates toward the two active sites, which may provide some selective advantage to the bifunctional enzyme beyond coexpression as a single polypeptide, likely linked to an improvement in enzymatic properties.