Resistance mechanisms

There are several ways for microorganisms to become resistant to antimicrobial agents, including antibiotics, and these can be considered intrinsic, adaptive, or acquired. This step will explore the ways that, bacteria specifically, may be resistant to the actions of antibiotics.

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Intrinsic resistance

Intrinsic resistance (sometimes called innate resistance) is a naturally occurring phenomenon and refers to the innate ability of a particular type of bacteria to resist the action of a family or type of antibiotic as a consequence of its structural or functional characteristics. Intrinsic resistance is not induced by the use of antibiotics and mechanisms of resistance can be enzymatic or non-enzymatic. Examples of characteristics that confer resistance include lack of drug targets, reduced permeability of the cell wall, efflux pumps or production of enzymes which break down the antibiotic as shown in the diagram below.

• As you learnt in week 1, anaerobes are intrinsically resistant to aminoglycosides. For aminoglycosides to cross bacterial cell walls, there must be an active electron transport chain sufficient to generate an electrical potential difference across the membrane. Therefore, as obligate anaerobes are unable to generate a sufficient electrical potential difference across the membrane, they are resistant.
• Mutations in the 16S rRNA may cause intrinsic resistance; the best-known example is the resistance of Mycobacterium tuberculosis to streptomycin as a result of point mutations in ribosomal protein S12 and in the 16S rRNA. Resistance of Mycobacterium abscessus and Mycobacterium chelonae to amikacin is the result of 16S rRNA point mutation
• Enzymatic resistance mechanisms are exemplified by the methylating enzymes that modify the 16S rRNA

Adaptive resistance

Adaptive resistance develops in response to environmental triggers, for example antibiotic administration, at subtherapeutic levels. Some bacteria may respond by expressing a resistant phenotype induced by a number of different mechanisms. For example, epigenetic alterations and transcriptional changes result in the bacterium having certain characteristics that make it transiently no longer susceptible to the antibiotic it was originally susceptible to. It is important to note that this is not inheritable.

Acquired resistance

Acquired resistance occurs through sporadic mutations or through the acquisition of foreign genetic material by horizontal gene or plasmid transfer in genes associated with antibiotic resistance. As a result, originally antibiotic-sensitive bacteria become resistant, and all daughter cells originating from them will also possess resistance. The administration of antibiotics provides a selective pressure that allows resistant variants to be better able to survive, allowing their population to proliferate.

The sporadic mutations or acquired genetic material will confer resistance due to sequence changes in codons responsible for encoding either the drug target, or part of the drug-uptake transport system.

Most drug resistance is due to a genetic change in the organism, either a chromosomal mutation or acquisition of a plasmid or transposon. The frequency of spontaneous mutations, however, is much lower than the frequency of acquisition of resistance plasmids. Therefore, plasmid–mediated resistance poses a higher clinical risk than chromosomal resistance.

• A plasmid is a small extrachromosomal DNA molecule, within a cell, that is physically separated from chromosomal DNA and can replicate independently
• Transposons are genes that are transferred either within or between larger pieces of DNA such as the bacterial chromosome and plasmid

Further detail on resistance mechanisms can be found in the PDF under downloads below.