Causative Agent And Classification Of Mutation

Cell A (resistant) Cell B (resistant)

Cell A (resistant) Cell B (resistant)

Cell C Cell C (resistant)

Figure 21.15 The Acquisition of Antimicrobial Resistance

(a) Spontaneous mutation, leading to vertical evolution. Only the progeny of the mutant cell are resistant (R). (b) Gene transfer, leading to horizontal evolution. Even unrelated bacteria can acquire resistance.

Spontaneous Mutation

As cells replicate, spontaneous mutations occur at a relatively low rate. Even at a low rate, however, such mutations can ultimately have a profound effect on the resistance of a bacterial population to an antimicrobial drug. For example, resistance to the aminoglycoside streptomycin results from a single base-pair change in the gene encoding the ribosomal protein to which streptomycin binds; that point mutation alters the target sufficiently to render the drug ineffective. When a streptomycin sensitive bacterium is grown in streptomycin-free medium to a population of 109 cells, it is probable that at least one cell in the population has that particular mutation in its genome. Through spontaneous mutation, that particular cell has acquired resistance to streptomycin. If streptomycin is then added to the medium, that cell but no others will be able to replicate, eventually generating a population of streptomycin-resistant clones.

When an antimicrobial drug has several different potential targets or has multiple binding sites on a single target, it is more difficult for an organism to develop resistance through spontaneous mutation. This is because several different mutations are required to prevent binding of the drug. Unlike streptomycin, the newer aminoglycosides bind to several sites on the ribosome, making resistance due to spontaneous mutation less likely.

Drugs such as streptomycin to which single point mutations can confer resistance are sometimes used in combination with another drug to prevent survival of resistant mutants. The chance of an organism simultaneously developing mutational resistance to each drug is extremely low. If any organism spontaneously develops resistance to one drug, the other drug will still kill it.

Gene Transfer

Given the mobility of DNA, genes encoding resistance to an antimicrobial drug can spread to different strains, species, and even genera. The most common mechanism of transfer of resistance is through the conjugative transfer of R plasmids. R plas-mids frequently carry several different resistance genes, each one mediating resistance to a specific antimicrobial drug. Thus, when an organism acquires an R plasmid, it acquires resistance to several different medications simultaneously. Many of the resistance genes on R plasmids are carried on transposons that can move from a plasmid to the chromosome, from one plasmid to another, or from the chromosome to a plasmid. Thus, if one organism has two different plasmids, an antibiotic-resistance gene can move from one to the other. In this way a gene could move from a narrow host range plasmid to a wide host range plasmid. Wide host range plasmids, in contrast to narrow host range plasmids, can replicate even if they are transferred to unrelated bacteria. ■ R plasmid, p. 210 ■ transposon, p. 212

In some cases, the resistance gene transferred from one organism to another originated through spontaneous mutation of a common bacterial gene, such as one encoding the target of the drug. In other cases, the gene may have originated from the soil microbe that naturally produces that antibiotic. For example, a gene coding for an enzyme that chemically modifies an aminoglycoside likely originated from the Streptomyces species that produces that aminoglycoside.

21.5 Resistance to Antimicrobial Drugs 523

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