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EcoSal Plus

Domain 4:

Synthesis and Processing of Macromolecules

Antibiotic Resistance Mechanisms, with an Emphasis on Those Related to the Ribosome

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  • Authors: Katherine S. Long1, and Birte Vester2
  • Editor: Susan T. Lovett3
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Biology, University of Copenhagen, Copenhagen Biocenter, 3-1-31, Ole Maaløes Vej 5, DK-2200 Copenhagen N, Denmark; 2: Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark; 3: Brandeis University, Waltham, MA
  • Received 13 December 2007 Accepted 27 February 2008 Published 26 August 2008
  • Address correspondence to Birte Vester b.vester@bmb.sdu.dk.
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  • Abstract:

    Antibiotic resistance is a fundamental aspect of microbiology, but it is also a phenomenon of vital importance in the treatment of diseases caused by pathogenic microorganisms. A resistance mechanism can involve an inherent trait or the acquisition of a new characteristic through either mutation or horizontal gene transfer. The natural susceptibilities of bacteria to a certain drug vary significantly from one species of bacteria to another and even from one strain to another. Once inside the cell, most antibiotics affect all bacteria similarly. The ribosome is a major site of antibiotic action and is targeted by a large and chemically diverse group of antibiotics. A number of these antibiotics have important applications in human and veterinary medicine in the treatment of bacterial infections. The antibiotic binding sites are clustered at functional centers of the ribosome, such as the decoding center, the peptidyl transferase center, the GTPase center, the peptide exit tunnel, and the subunit interface spanning both subunits on the ribosome. Upon binding, the drugs interfere with the positioning and movement of substrates, products, and ribosomal components that are essential for protein synthesis. Ribosomal antibiotic resistance is due to the alteration of the antibiotic binding sites through either mutation or methylation. Our knowledge of antibiotic resistance mechanisms has increased, in particular due to the elucidation of the detailed structures of antibiotic-ribosome complexes and the components of the efflux systems. A number of mutations and methyltransferases conferring antibiotic resistance have been characterized. These developments are important for understanding and approaching the problems associated with antibiotic resistance, including design of antimicrobials that are impervious to known bacterial resistance mechanisms.

  • Citation: Long K, Vester B. 2008. Antibiotic Resistance Mechanisms, with an Emphasis on Those Related to the Ribosome, EcoSal Plus 2008; doi:10.1128/ecosalplus.2.5.7

Key Concept Ranking

Small Multidrug Resistance Family
0.5409483
Major Facilitator Superfamily
0.4137931
Outer Membrane Proteins
0.3628107
0.5409483

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ecosalplus.2.5.7.citations
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/content/journal/ecosalplus/10.1128/ecosalplus.2.5.7
2008-08-26
2017-03-25

Abstract:

Antibiotic resistance is a fundamental aspect of microbiology, but it is also a phenomenon of vital importance in the treatment of diseases caused by pathogenic microorganisms. A resistance mechanism can involve an inherent trait or the acquisition of a new characteristic through either mutation or horizontal gene transfer. The natural susceptibilities of bacteria to a certain drug vary significantly from one species of bacteria to another and even from one strain to another. Once inside the cell, most antibiotics affect all bacteria similarly. The ribosome is a major site of antibiotic action and is targeted by a large and chemically diverse group of antibiotics. A number of these antibiotics have important applications in human and veterinary medicine in the treatment of bacterial infections. The antibiotic binding sites are clustered at functional centers of the ribosome, such as the decoding center, the peptidyl transferase center, the GTPase center, the peptide exit tunnel, and the subunit interface spanning both subunits on the ribosome. Upon binding, the drugs interfere with the positioning and movement of substrates, products, and ribosomal components that are essential for protein synthesis. Ribosomal antibiotic resistance is due to the alteration of the antibiotic binding sites through either mutation or methylation. Our knowledge of antibiotic resistance mechanisms has increased, in particular due to the elucidation of the detailed structures of antibiotic-ribosome complexes and the components of the efflux systems. A number of mutations and methyltransferases conferring antibiotic resistance have been characterized. These developments are important for understanding and approaching the problems associated with antibiotic resistance, including design of antimicrobials that are impervious to known bacterial resistance mechanisms.

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Figures

Image of Figure 1
Figure 1

The cell membrane is depicted in grey, ribosomes are depicted in green, mRNA is depicted in red, and a fictitious antibiotic that targets ribosomes is shown in blue. (i) The antibiotic is pumped out of the cell, lowering the intracellular antibiotic concentration and thereby antibiotic binding to ribosomes. (ii) The antibiotic is inactivated so that it cannot bind to its target and inhibit protein synthesis. (iii) The drug binding sites on the ribosomes (illustrated with white diamonds) are changed so that the drug does not bind and therefore does not inhibit protein synthesis.

Citation: Long K, Vester B. 2008. Antibiotic Resistance Mechanisms, with an Emphasis on Those Related to the Ribosome, EcoSal Plus 2008; doi:10.1128/ecosalplus.2.5.7
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Image of Figure 2
Figure 2

The efflux system consists of an outer membrane protein (TolC or OprM), an efflux protein (AcrB or MexB), and membrane fusion proteins (AcrA and MexA).

Citation: Long K, Vester B. 2008. Antibiotic Resistance Mechanisms, with an Emphasis on Those Related to the Ribosome, EcoSal Plus 2008; doi:10.1128/ecosalplus.2.5.7
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Image of Figure 3
Figure 3

In the panels depicting the individual subunits and the assembled ribosome, proteins are shown in yellow and cobalt blue, and RNA is shown in orange and light blue for the 30S and 50S subunits, respectively. The antibiotic binding sites mentioned in the text in relation to resistance determinants are indicated with arrows. The coordinates for the whole subunits () are from reference 21 ; the coordinates for the cut view () are from reference 22 . The models were kindly provided by Jacob Poehlsgaard using VMD ( 23 ).

Citation: Long K, Vester B. 2008. Antibiotic Resistance Mechanisms, with an Emphasis on Those Related to the Ribosome, EcoSal Plus 2008; doi:10.1128/ecosalplus.2.5.7
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Image of Figure 4
Figure 4

A bacterial cell is depicted with a translating ribosome (top left panel). The antimicrobial drugs inhibit bacterial growth by binding to ribosomes and blocking protein synthesis. The structure of the bacterial 50S ribosomal subunit ( 21 ) and an expanded view with the structures of the four drugs (depicted in stick form according to the color scheme shown in the bottom panels) bound at the PTC (top right panel) are shown. The target of the Cfr methyltransferase causing resistance, nucleotide A2503, is shown in red. The surrounding RNA is shown in light grey. In the bottom panels, the names and chemical structures of the four antimicrobial agents are shown with background colors that correspond to those of their bound structures depicted in the expanded view. References for the antibiotic-50S subunit complexes are cited in the text.

Citation: Long K, Vester B. 2008. Antibiotic Resistance Mechanisms, with an Emphasis on Those Related to the Ribosome, EcoSal Plus 2008; doi:10.1128/ecosalplus.2.5.7
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Tables

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Table 1

rRNA methyltransferases associated with antibiotic resistance in bacteria

Citation: Long K, Vester B. 2008. Antibiotic Resistance Mechanisms, with an Emphasis on Those Related to the Ribosome, EcoSal Plus 2008; doi:10.1128/ecosalplus.2.5.7

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