Genetic mechanisms of acquired antimicrobial resistance (the title of the page was rephrased as the content is about the mechanisms of resistance rather than about genetic mechanisms)

1. Prevention of the antimicrobial from reaching its target by reducing its ability to penetrate into the cell

Antimicrobial compounds almost always require access into the bacterial cell to reach their target site where they can interfere with the normal function of the bacterial organism. Porin channels are the passageways by which these antibiotics would normally cross the bacterial outer membrane. Some bacteria protect themselves by prohibiting these antimicrobial compounds from entering past their cell walls. For example, a variety of Gram-negative bacteria reduce the uptake of certain antibiotics, such as aminoglycosides and beta lactams, by modifying the cell membrane porin channel frequency, size, and selectivity. Prohibiting entry in this manner will prevent these antimicrobials from reaching their intended targets that, for aminoglycosides and beta lactams, are the ribosomes and the penicillin-binding proteins (PBPs), respectively.

This strategy have been observed in:

  • Pseudomonas aeruginosa e.g. against imipenem (a beta-lactam antibiotic);
  • Enterobacter aerogenes and Klebsiella spp. against imipenem;
  • glycopeptide intermediate-resistant S. aureus so-called  “GISA” strains with thickened cell wall trapping vancomycin/teicoplanin;
  • many Gram-negative bacteria against aminoglycosides;
  • many Gram-negative bacteria against quinolones.

 2. Inactivation of antimicrobial agents via modification or degradation

Another means by which bacteria preserve themselves is by destroying the active component of the antimicrobial agent. A classic example is the hydrolytic deactivation of the beta-lactam ring in penicillins and cephalosporins by the bacterial enzyme called beta lactamase. The inactivated penicilloic acid will then be ineffective in binding to PBPs (penicillin binding proteins), thereby protecting the process of cell wall synthesis. This strategy has also been observed in:

  • Enterobacteriaceae against chloramphenicol (acetylation)
  • Gram negative and Gram positive bacteria against aminoglycosides (phosphorylation, adenylation, and acetylation).

 3. Expulsion of the antimicrobial agents from the cell via general or specific efflux pumps

To be effective, antimicrobial agents must also be present at a sufficiently high concentration within the bacterial cell. Some bacteria possess membrane proteins that act as an export or efflux pump for certain antimicrobials, extruding the antibiotic out of the cell as fast as it can enter. This results in low intracellular concentrations that are insufficient to elicit an effect. Some efflux pumps selectively extrude specific antibiotics such as macrolides, lincosamides, streptogramins and tetracyclines, whereas others (referred to as multiple drug resistance pumps) expel a variety of structurally diverse anti-infectives with different modes of action e.g. the qac genes which pump out chlorhexidine, propamidine and quaternary ammonium agents. This strategy has also been observed in:

  • E. coli and other Enterobacteriaceae against tetracyclines;
  • Various members of the Enterobacteriaceae against chloramphenicol;
  • Staphylococci against macrolides and streptogramins;
  • Staphylococcus aureus and Streptococcus pneumoniae against fluoroquinolones.

4. Modification of the antimicrobial target within the bacteria

Some resistant bacteria evade antimicrobials by reprogramming or camouflaging critical target sites to avoid recognition. Therefore, in spite of the presence of an intact and active antimicrobial compound, no subsequent binding or inhibition will take place. This strategy has been observed in:

  • Staphylococci against methicillin and other beta-lactams (Changes or acquisition of different PBPs that do not sufficiently bind beta-lactams to inhibit cell wall synthesis);
  • Gram-positive cocci: erythromycin-resistant methylase is encoded by erm genes and causes structural changes to rRNA which prevent macrolide binding and allow synthesis of bacterial proteins to continue;
  • Enterococci against vancomycin (alteration in cell wall precursor components to decrease binding of vancomycin);
  • Mycobacterium spp. against streptomycin (modification of ribosomal proteins or of 16s rRNA);
  • Various microbes which develop mutations in RNA polymerase resulting in resistance to the rifamycins e.g.Staphylococcus spp;
  • members of Enterobacteriaceae  with mutations in DNA gyrase resulting in resistance to quinolones

 

Link to European IC/HH Core Competencies: Area 4. Infection control activities

References: not provided yet.