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Overview of the mechanisms of AMR

Before we can understand how to prevent AMR, we need to understand how it occurs. Nicola Williams will cover this concept in this article.

Antibiotics are ‘magic bullets’ with the aim of targeting parts of the bacterial physiology that are not present in eukaryotic cells. This minimises damage to the host.

Diagram showing the main targets of antibiotics to parts of the bacterial physiology. these include: DNA synthesis, protein synthesis and the outer membrane. Click to enlarge

Image showing the main bacterial mechanisms of resistance to antimicrobials including decreased permeability, enzymatic inactivation and altered targets. Click to enlarge

Antimicrobial resistance can be intrinsic or acquired by bacteria.

Intrinsic resistance

Intrinsic AMR represents an inherent or natural trait found in some bacteria that makes antibiotics ineffective against them. For example, the Mycoplasma species, which cause a range of infections in different animal species, lack a cell wall. The β-lactam family of drugs target the bacterial cell wall and therefore, would not have any effect on Mycoplasma species. A further example is innate production of enzymes that can inactivate a drug, such as Klebsiella species and ampicillin resistance.

Other key examples include:

  • Metronidazole and aerobes.

  • Aminoglycosides and anaerobic bacteria.

  • Cephalosporins and enterococci.

Acquired antimicrobial resistance

Intrinsic resistance is easy to predict if you know the organism associated with an infection; it is arguably more difficult to predict a resistance pattern when resistance is acquired by a bacteria.

AMR can be acquired via mutation(s) or by acquiring new genetic material. AMR acquired through mutation can not, however, be passed between bacteria, but only via replication to new generations of that bacteria. Of more concern is resistance acquired via a mobile genetic element (e.g. plasmids), as in this case multiple antibiotic resistance genes maybe present on the same element, rendering the bacteria resistant to multiple classes of drug.

AMR may arise from mutation(s) in a gene which:

  • encodes a target site.
  • alters an outer membrane protein which prevents the drug getting into the bacterial cell and accessing its intracellular target.
  • leads to overexpression of efflux pumps which reduce the intracellular concentration of the antibiotic.
  • leads to overexpression of the antibiotic target.

AMR does not usually develop in vivo in the pathogen during treatment of infection, with the main exceptions to this being with the fluoroquinolone class of drugs and rifampicin.

Mutant prevention concentration

Where bacteria are present in high numbers, mutations can arise spontaneously and then such bacteria are selected for within that population under antibiotic selective pressure.

The mutant prevention concentration (MPC) is the lowest concentration of drug required to stop the growth of the least susceptible bacterial cell within a high density bacterial population.

Graph showing how the length of time the drug stays in the mutant selection window will effect the liklihood for drug resistant selection. Click to enlarge

For an interesting case study on Campylobacter species, fluoroquinolone resistance and poultry, please see the document in the see also section below.

Biofilms and antimicrobial resistance

Some bacteria are able to produce biofilms, either alone or with other microorganisms. Biofilms are microbial communities which attach to abiotic (e.g. indwelling devices) and biotic surfaces (e.g. wound tissues) and which can be protected by a polymer layer. When present, biofilms can increase the concentration of antibiotics required to kill or stop bacteria growing:

  • Antibiotics may not infiltrate the biofilm as easily.
  • Bacteria may be much more slow-growing so they are less susceptible to drugs requiring cell growth.
  • Due to oxidative stress within the biofilm, bacteria may develop mutations at a higher rate.

In conclusion

  • Antibiotics target a number of different processes within bacteria which results in their death or prevents them growing.

  • Bacteria have evolved a number of different mechanisms to resist the effects of antibiotics, by reducing the intracellular concentration, or by preventing the antibiotic binding to its target.

  • Resistance can develop due to mutations, or by bacteria acquiring new genetic material encoding resistance.

  • Maintaining dosing is important for some antibiotics in minimising the selection of antibiotic resistant mutants in high density bacterial populations.

  • If bacteria are in a biofilm they may be more resistant to antibiotics and require higher doses of drug.

If you have any questions on this content, please feel free to ask them in the comments section below.

In the next step, we will look at why AMR has emerged and how it can be transmitted, both between animals and between bacteria.

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Antimicrobial Stewardship in Veterinary Practice


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