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Mechanisms of Antibiotic Resistance

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  • Authors: Jose M. Munita1,2,3, Cesar A. Arias4,5,6
  • Editors: Indira T. Kudva7, Qijing Zhang8
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical School at Houston, Houston, TX 77030; 2: International Center for Microbial Genomics; 3: Clinica Alemana de Santiago, Universidad del Desarrollo School of Medicine, Santiago, Chile; 4: Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical School at Houston, Houston, TX 77030; 5: International Center for Microbial Genomics; 6: Molecular Genetics and Antimicrobial Resistance Unit, Universidad El Bosque, Bogota, Colombia; 7: National Animal Disease Center, Agricultural Research Service, U.S. Department of Agriculture, Ames, IA; 8: Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA
    • Source: microbiolspec April 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0016-2015
  • Received 20 April 2015 Accepted 27 July 2015 Published 08 April 2016
  • Cesar A. Arias, [email protected]
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  • Abstract:

    Emergence of resistance among the most important bacterial pathogens is recognized as a major public health threat affecting humans worldwide. Multidrug-resistant organisms have not only emerged in the hospital environment but are now often identified in community settings, suggesting that reservoirs of antibiotic-resistant bacteria are present outside the hospital. The bacterial response to the antibiotic “attack” is the prime example of bacterial adaptation and the pinnacle of evolution. “Survival of the fittest” is a consequence of an immense genetic plasticity of bacterial pathogens that trigger specific responses that result in mutational adaptations, acquisition of genetic material, or alteration of gene expression producing resistance to virtually all antibiotics currently available in clinical practice. Therefore, understanding the biochemical and genetic basis of resistance is of paramount importance to design strategies to curtail the emergence and spread of resistance and to devise innovative therapeutic approaches against multidrug-resistant organisms. In this chapter, we will describe in detail the major mechanisms of antibiotic resistance encountered in clinical practice, providing specific examples in relevant bacterial pathogens.

  • Citation: Munita J, Arias C. 2016. Mechanisms of Antibiotic Resistance. Microbiol Spectrum 4(2):VMBF-0016-2015. doi:10.1128/microbiolspec.VMBF-0016-2015.

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/content/journal/microbiolspec/10.1128/microbiolspec.VMBF-0016-2015
2016-04-08
2020-02-17

Abstract:

Emergence of resistance among the most important bacterial pathogens is recognized as a major public health threat affecting humans worldwide. Multidrug-resistant organisms have not only emerged in the hospital environment but are now often identified in community settings, suggesting that reservoirs of antibiotic-resistant bacteria are present outside the hospital. The bacterial response to the antibiotic “attack” is the prime example of bacterial adaptation and the pinnacle of evolution. “Survival of the fittest” is a consequence of an immense genetic plasticity of bacterial pathogens that trigger specific responses that result in mutational adaptations, acquisition of genetic material, or alteration of gene expression producing resistance to virtually all antibiotics currently available in clinical practice. Therefore, understanding the biochemical and genetic basis of resistance is of paramount importance to design strategies to curtail the emergence and spread of resistance and to devise innovative therapeutic approaches against multidrug-resistant organisms. In this chapter, we will describe in detail the major mechanisms of antibiotic resistance encountered in clinical practice, providing specific examples in relevant bacterial pathogens.

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Mechanisms of Antibiotic Resistance
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Citation: Munita J, Arias C. 2016. Mechanisms of antibiotic resistance. microbiolspec 4(2): doi:10.1128/microbiolspec.VMBF-0016-2015
/content/microbiolspec/10.1128/microbiolspec.VMBF-0016-2015.fig1
FIGURE 1
Representation of different types of aminoglycoside-modifying enzymes and their nomenclature. Each group of enzymes is identified by their biochemical activity as follows: acetyltransferase (AAC), adenyltransferase (ANT), and phosphotransferase (APH). Next in the enzyme name, an algebraic number in parentheses indicates the number of the carbon that is inactivated. The ring of the sugar in which the reaction takes place is symbolized by one (first sugar moiety) or two apostrophes (second sugar moiety). Roman numerals are used to differentiate distinct isoenzymes acting in the same site. Not all existing enzymes are shown. A, amikacin; G, gentamicin; I, isepamicin; K, kanamycin; N, netilmicin; S, sisomicin; T, tobramycin. Modified from reference 106 .
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FIGURE 1

Representation of different types of aminoglycoside-modifying enzymes and their nomenclature. Each group of enzymes is identified by their biochemical activity as follows: acetyltransferase (AAC), adenyltransferase (ANT), and phosphotransferase (APH). Next in the enzyme name, an algebraic number in parentheses indicates the number of the carbon that is inactivated. The ring of the sugar in which the reaction takes place is symbolized by one (first sugar moiety) or two apostrophes (second sugar moiety). Roman numerals are used to differentiate distinct isoenzymes acting in the same site. Not all existing enzymes are shown. A, amikacin; G, gentamicin; I, isepamicin; K, kanamycin; N, netilmicin; S, sisomicin; T, tobramycin. Modified from reference 106 .

Source: microbiolspec April 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0016-2015
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FIGURE 2
Schematic representation of β-lactamases. Molecular classification of β-lactamases follows the Ambler classification. Correlation with the main functional group of the Bush and Jacobi classification is also shown. Of note, the latter classification has several subgroups that are not shown. Representative examples of each group of enzymes are provided. Class A enzymes are the most diverse and include penicillinases, ESBLs, and carbapenemases. Ambler class D enzymes belong to the functional group/subgroup 2d. *Class A enzymes belonging to the subgroup 2br are resistant to clavulanic acid inhibition. EDTA, ethylenediaminetetraacetic acid; ESBLs, extended-spectrum β-lactamases.
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FIGURE 2

Schematic representation of β-lactamases. Molecular classification of β-lactamases follows the Ambler classification. Correlation with the main functional group of the Bush and Jacobi classification is also shown. Of note, the latter classification has several subgroups that are not shown. Representative examples of each group of enzymes are provided. Class A enzymes are the most diverse and include penicillinases, ESBLs, and carbapenemases. Ambler class D enzymes belong to the functional group/subgroup 2d. *Class A enzymes belonging to the subgroup 2br are resistant to clavulanic acid inhibition. EDTA, ethylenediaminetetraacetic acid; ESBLs, extended-spectrum β-lactamases.

Source: microbiolspec April 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0016-2015
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FIGURE 3
Representation of different types of efflux pumps in Gram-positive and Gram-negative bacteria. The five major families of efflux pumps are shown: ATP-binding cassette (ABC) superfamily, the major facilitator superfamily (MFS), the multidrug and toxic-compound extrusion (MATE) family, the small multidrug resistance (SMR) family, and the resistance nodulation division (RND) family. A diagrammatic comparison of all the families showing their source of energy and examples of drugs and compounds that serve as a substrate are shown. Modified from reference 107 with permission.
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FIGURE 3

Representation of different types of efflux pumps in Gram-positive and Gram-negative bacteria. The five major families of efflux pumps are shown: ATP-binding cassette (ABC) superfamily, the major facilitator superfamily (MFS), the multidrug and toxic-compound extrusion (MATE) family, the small multidrug resistance (SMR) family, and the resistance nodulation division (RND) family. A diagrammatic comparison of all the families showing their source of energy and examples of drugs and compounds that serve as a substrate are shown. Modified from reference 107 with permission.

Source: microbiolspec April 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0016-2015
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FIGURE 4
Schematic representation of the mechanism of action and resistance to linezolid. Linezolid interferes with the positioning of aminoacyl-tRNA by interactions with the peptidyl-transferase center (PTC). Ribosomal proteins L3 and L4 associated with resistance are shown. Representation of domain V of 23S rRNA showing mutations associated with linezolid resistance. Position A2503, which is the target of Cfr methylation, is highlighted. Adapted from reference 92 .
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FIGURE 4

Schematic representation of the mechanism of action and resistance to linezolid. Linezolid interferes with the positioning of aminoacyl-tRNA by interactions with the peptidyl-transferase center (PTC). Ribosomal proteins L3 and L4 associated with resistance are shown. Representation of domain V of 23S rRNA showing mutations associated with linezolid resistance. Position A2503, which is the target of Cfr methylation, is highlighted. Adapted from reference 92 .

Source: microbiolspec April 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0016-2015
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FIGURE 5
Schematic representation of the posttranscriptional control of the gene. Under noninducing conditions, the ErmC leader peptide is produced and the mRNA forms two hairpins, preventing the ribosome from recognizing the ribosomal binding site (RBS) of . As a result, translation is inhibited. After exposure to erythromycin (EM, yellow star), the antibiotic interacts with the ribosome and binds tightly to the leader peptide, stalling progression of translation. This phenomenon releases the RBS and permits translation. RBS, ribosomal binding site of the leader; RBS, ribosomal binding site of ; AUG, initiation codon. Ribosome represented in blue and erythromycin in yellow.
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FIGURE 5

Schematic representation of the posttranscriptional control of the gene. Under noninducing conditions, the ErmC leader peptide is produced and the mRNA forms two hairpins, preventing the ribosome from recognizing the ribosomal binding site (RBS) of . As a result, translation is inhibited. After exposure to erythromycin (EM, yellow star), the antibiotic interacts with the ribosome and binds tightly to the leader peptide, stalling progression of translation. This phenomenon releases the RBS and permits translation. RBS, ribosomal binding site of the leader; RBS, ribosomal binding site of ; AUG, initiation codon. Ribosome represented in blue and erythromycin in yellow.

Source: microbiolspec April 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0016-2015
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FIGURE 6
Schematic representation of peptidoglycan biosynthesis and mechanisms of vancomycin action and resistance . Normal peptidoglycan production. Binding of the antibiotic to the terminal -Ala--Ala of the peptidoglycan precursors prevents transpeptidation and transglycosylation, interrupting cell wall synthesis and resulting in bacterial death. The change in peptidoglycan synthesis produced by the expression of the gene cluster. Change of the terminal dipeptide from -Ala--Ala to -Ala--Lac markedly reduces the binding of vancomycin to the peptidoglycan target permitting cell wall synthesis to continue.
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FIGURE 6

Schematic representation of peptidoglycan biosynthesis and mechanisms of vancomycin action and resistance . Normal peptidoglycan production. Binding of the antibiotic to the terminal -Ala--Ala of the peptidoglycan precursors prevents transpeptidation and transglycosylation, interrupting cell wall synthesis and resulting in bacterial death. The change in peptidoglycan synthesis produced by the expression of the gene cluster. Change of the terminal dipeptide from -Ala--Ala to -Ala--Lac markedly reduces the binding of vancomycin to the peptidoglycan target permitting cell wall synthesis to continue.

Source: microbiolspec April 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0016-2015
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FIGURE 7
Diagrammatic representation of the mechanism of action of daptomycin. DAP, daptomycin; PG, phosphatidylglycerol; CM, cell membrane.
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FIGURE 7

Diagrammatic representation of the mechanism of action of daptomycin. DAP, daptomycin; PG, phosphatidylglycerol; CM, cell membrane.

Source: microbiolspec April 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0016-2015
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