Mechanisms of Antibiotic Resistance

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.

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 (ACC), adenyltransferase (ANT) and phosphotransferase (APH). Next in the enzyme name, an algebraic number in parenthesis 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 Appl Microbiol Biotechnol (2006)70:140–150.

Figure 2. Schematic representation of β-lactamases

Molecular classification of B-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 sub-groups 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, ehtylenediaminetetraacetic acid; ESBLs, extended-spectrum β-lactamases

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 Piddock LJ. Nat Rev Microbiol. 2006;4(8):629–36 with permission.

Figure 4. Schematic representation of the mechanism of action and resistance to linezolid

Panel A. 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. Panel B. Representation of domain V of 23S rRNA showing mutations associated with linezolid resistance. Position A2503, which is the target of Cfr methylation, is highlighted.

Figure 5. Schematic representation of the post-transcriptional control of the ermC gene

Under non-inducing conditions, the ErmC leader peptide is produced and the ermC mRNA forms two hairpins, preventing the ribosome to recognize the ribosomal binding site (RBS) of ermC. 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 ermC RBS and permits translation. RBS_L, ribosomal binding site of the leader; RBS_C, ribosomal binding site of ermC; AUG, initiation codon. Ribosome represented in blue and erythromycin in yellow.

Figure 6. Schematic representation of peptidoglycan biosynthesis and mechanisms of vancomycin action (A) and resistance (B)

Panel A depicts normal peptidoglycan production and shows that binding of the antibiotic to the terminal D-Ala-D-Ala of the peptidoglycan precursors prevents transpeptidation and transglycosylation, interrupting cell wall synthesis and resulting in bacterial death. Panel B shows the change in peptidoglycan synthesis produced by the expression of the vanA gene cluster. Change of the terminal dipeptide from D-Ala-D-Ala to D-Ala-D-Lac markedly reduces the binding of vancomycin to the peptidoglycan target permitting cell wall synthesis to continue.

Figure 7

Diagrammatic representation of the mechanism of action of daptomycin.