Mechanisms::Antimicrobial resistance


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Schematic representation of how antibiotic resistance evolves via natural selection. The top section represents a population of bacteria before exposure to an antibiotic. The middle section shows the population directly after exposure, the phase in which selection took place. The last section shows the distribution of resistance in a new generation of bacteria. The legend indicates the resistance levels of individuals.
Diagram depicting antibiotic resistance through alteration of the antibiotic's target site, modeled after MRSA's resistance to penicillin. Beta-lactam antibiotics permanently inactivate PBP enzymes, which are essential for bacterial life, by permanently binding to their active sites. MRSA, however, expresses a PBP that does not allow the antibiotic into its active site.

The four main mechanisms by which microorganisms exhibit resistance to antimicrobials are:

  1. Drug inactivation or modification: for example, enzymatic deactivation of penicillin G in some penicillin-resistant bacteria through the production of β-lactamases. Most commonly, the protective enzymes produced by the bacterial cell will add an acetyl or phosphate group to a specific site on the antibiotic, which will reduce its ability to bind to the bacterial ribosomes and disrupt protein synthesis.<ref name="Criswell, Daniel 2004">[Criswell, Daniel. "The "Evolution" of Antibiotic Resistance." Institute for Creation Research. N.p., 2004. Web. 28 Oct. 2014.]</ref>
  2. Alteration of target site: for example, alteration of PBP—the binding target site of penicillins—in MRSA and other penicillin-resistant bacteria. Another protective mechanism found among bacterial species is ribosomal protection proteins. These proteins protect the bacterial cell from antibiotics that target the cell’s ribosomes to inhibit protein synthesis. The mechanism involves the binding of the ribosomal protection proteins to the ribosomes of the bacterial cell, which in turn changes its conformational shape. This allows the ribosomes to continue synthesizing proteins essential to the cell while preventing antibiotics from binding to the ribosome to inhibit protein synthesis.
  3. Alteration of metabolic pathway: for example, some sulfonamide-resistant bacteria do not require para-aminobenzoic acid (PABA), an important precursor for the synthesis of folic acid and nucleic acids in bacteria inhibited by sulfonamides, instead, like mammalian cells, they turn to using preformed folic acid.
  4. Reduced drug accumulation: by decreasing drug permeability or increasing active efflux (pumping out) of the drugs across the cell surface<ref>{{#invoke:Citation/CS1|citation

|CitationClass=journal }}</ref> These specialized pumps can be found within the cellular membrane of certain bacterial species and are used to pump antibiotics out of the cell before they are able to do any damage. These efflux pumps are often activated by a specific substrate associated with an antibiotic.<ref>[RI Aminov, RI Mackie. Evolution and ecology of antibiotic resistance genes. Microbiology Letters. 8 May 2007. doi:10.1111/j.1574-6968.2007.00757.x]</ref>

A number of mechanisms used by common antibiotics to deal with bacteria and ways by which bacteria become resistant to them.

Antibiotic resistance can be a result of horizontal gene transfer,<ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }} </ref> and also of unlinked point mutations in the pathogen genome at a rate of about 1 in 108 per chromosomal replication. Mutations are rare but the fact that bacteria reproduce at such a high rate allows for the effect to be significant. A mutation may produce a change in the binding site of the antibiotic, which may allow the site to continue proper functioning in the presence of the antibiotic or prevent the binding of the antibiotic to the site altogether. Research has shown the bacterial protein LexA may play a key role in the acquisition of bacterial mutations giving resistance to quinolones and rifampicin. DNA damage induces the SOS gene repressor LexA to undergo autoproteolytic activity. This includes the transcription of genes encoding Pol II, Pol IV, and Pol V, which are three nonessential DNA polymerases that are required for mutation in response to DNA damage.<ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> The antibiotic action against the pathogen can be seen as an environmental pressure. Those bacteria with a mutation that allows them to survive live to reproduce. They then pass this trait to their offspring, which leads to the evolution of a fully resistant colony. Although these chromosomal mutations may seem to benefit the bacteria by providing antibiotic resistance, they also confer a cost of fitness. For example, a ribosomal mutation may protect a bacterial cell by changing the binding site of an antibiotic but it will also slow the process of protein synthesis.<ref name="Criswell, Daniel 2004"/> Additionally, a particular study specifically compared the overall fitness of antibiotic resistant strains of Escherichia coli and Salmonella typhimurium to their drug-sensitive revertants. They observed a reduced overall fitness in the antibiotic resistant strains, especially in growth rate.<ref>BR Levin, V Perrot, Nina Walker. Compensatory Mutations, Antibiotic Resistance and the Population Genetics of Adaptive Evolution in Bacteria. Genetics March 1, 2000 vol. 154 no. 3 985–997.</ref>

There are three known mechanisms of fluoroquinolone resistance. Some types of efflux pumps can act to decrease intracellular quinolone concentration.<ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> In Gram-negative bacteria, plasmid-mediated resistance genes produce proteins that can bind to DNA gyrase, protecting it from the action of quinolones. Finally, mutations at key sites in DNA gyrase or topoisomerase IV can decrease their binding affinity to quinolones, decreasing the drug's effectiveness.<ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref>

Antibiotic resistance can also be introduced artificially into a microorganism through laboratory protocols, sometimes used as a selectable marker to examine the mechanisms of gene transfer or to identify individuals that absorbed a piece of DNA that included the resistance gene and another gene of interest. A recent study demonstrated that the extent of horizontal gene transfer among Staphylococcus is much greater than previously expected—and encompasses genes with functions beyond antibiotic resistance and virulence, and beyond genes residing within the mobile genetic elements.<ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref>

For a long time, it has been thought that, for a microorganism to become resistant to an antibiotic, it must be in a large population. However, recent findings show that there is no necessity of large populations of bacteria for the appearance of antibiotic resistance. We know now that small populations of E.coli in an antibiotic gradient can become resistant. Any heterogeneous environment with respect to nutrient and antibiotic gradients may facilitate the development of antibiotic resistance in small bacterial populations and this is also true for the human body. Researchers hypothesize that the mechanism of resistance development is based on four SNP mutations in the genome of E.coli produced by the gradient of antibiotic. These mutations confer the bacteria emergence of antibiotic resistance.

Antimicrobial resistance sections
Intro  Definition  Causes  Environmental impact  Prevention  Mechanisms  Organisms  Applications  Society and culture  See also  Footnotes  References  External links  

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