Chapter 17 : Mechanisms of Antibiotic Resistance

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Mechanisms of Antibiotic Resistance, Page 1 of 2

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The discovery, commercialization, and routine administration of antimicrobial compounds to treat infections revolutionized modern medicine and changed the therapeutic paradigm. Indeed, antibiotics have become one of the most important medical interventions needed for the development of complex medical approaches such as cutting-edge surgical procedures, solid organ transplantation, and management of patients with cancer, among others. Unfortunately, the marked increase in antimicrobial resistance among common bacterial pathogens is now threatening this therapeutic accomplishment, jeopardizing the successful outcomes of critically ill patients. In fact, the World Health Organization has named antibiotic resistance as one of the three most important public health threats of the 21st century ( ).

Citation: Munita J, Arias C. 2016. Mechanisms of Antibiotic Resistance, p 481-511. In Kudva I, Cornick N, Plummer P, Zhang Q, Nicholson T, Bannantine J, Bellaire B (ed), Virulence Mechanisms of Bacterial Pathogens. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.VMBF-0016-2015
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Image of Figure 1
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 .

Citation: Munita J, Arias C. 2016. Mechanisms of Antibiotic Resistance, p 481-511. In Kudva I, Cornick N, Plummer P, Zhang Q, Nicholson T, Bannantine J, Bellaire B (ed), Virulence Mechanisms of Bacterial Pathogens. ASM Press, Washington, DC. 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.

Citation: Munita J, Arias C. 2016. Mechanisms of Antibiotic Resistance, p 481-511. In Kudva I, Cornick N, Plummer P, Zhang Q, Nicholson T, Bannantine J, Bellaire B (ed), Virulence Mechanisms of Bacterial Pathogens. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.VMBF-0016-2015
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Image of Figure 3
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 with permission.

Citation: Munita J, Arias C. 2016. Mechanisms of Antibiotic Resistance, p 481-511. In Kudva I, Cornick N, Plummer P, Zhang Q, Nicholson T, Bannantine J, Bellaire B (ed), Virulence Mechanisms of Bacterial Pathogens. ASM Press, Washington, DC. 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 .

Citation: Munita J, Arias C. 2016. Mechanisms of Antibiotic Resistance, p 481-511. In Kudva I, Cornick N, Plummer P, Zhang Q, Nicholson T, Bannantine J, Bellaire B (ed), Virulence Mechanisms of Bacterial Pathogens. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.VMBF-0016-2015
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Image of Figure 5
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.

Citation: Munita J, Arias C. 2016. Mechanisms of Antibiotic Resistance, p 481-511. In Kudva I, Cornick N, Plummer P, Zhang Q, Nicholson T, Bannantine J, Bellaire B (ed), Virulence Mechanisms of Bacterial Pathogens. ASM Press, Washington, DC. 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.

Citation: Munita J, Arias C. 2016. Mechanisms of Antibiotic Resistance, p 481-511. In Kudva I, Cornick N, Plummer P, Zhang Q, Nicholson T, Bannantine J, Bellaire B (ed), Virulence Mechanisms of Bacterial Pathogens. ASM Press, Washington, DC. 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.

Citation: Munita J, Arias C. 2016. Mechanisms of Antibiotic Resistance, p 481-511. In Kudva I, Cornick N, Plummer P, Zhang Q, Nicholson T, Bannantine J, Bellaire B (ed), Virulence Mechanisms of Bacterial Pathogens. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.VMBF-0016-2015
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