Chromosome-Mediated Resistance Chromosomal mutations in genes that encode for either the target of the drug or the transport system that controls the uptake of the drug can lead to resistance. The frequency of spontaneous chromosomal mutations is typically low due to the high fidelity of the DNA replication machinery in bacteria, usually ranging from 10−7 to 10−9. This is much lower than the frequency of resistance plasmid acquisition.
Some infections are simultaneously treated with two or more drugs. If the frequency that a bacterium mutates to become resistant to antibiotic A is 10−7 (1 in 10 million) and the frequency that the same bacterium mutates to become resistant to antibiotic B (operating under a different mechanism) is 10−8 (1 in 100 million), then the chance that the bacterium will become resistant to both antibiotics is the product of the two probabilities, or 10−15. It is highly unlikely that a bacterium will become resistant to both antibiotics when treated simultaneously.
Plasmid-Mediated Resistance
Plasmid-mediated resistance is clinically very important:
(1) It occurs in many different species, especially gram negative rods.
(2) Plasmids frequently mediate resistance to multiple drugs.
(3) Plasmids have a high rate of transfer from one cell to another, usually by conjugation.
Resistance plasmids (resistance factors, R factors) are extrachromosomal, circular, double-stranded DNA molecules that carry genes for a variety of enzymes that degrade antibiotics and modify membrane transport systems (Figure 1). Table 1 describes the most important mechanisms of resistance for several important drugs.
Fig1. Resistance plasmid (R plasmid, R factor). Most resistance plasmids have two sets of genes: (1) resistance transfer genes that encode the sex pilus and other proteins that mediate transfer of the plasmid DNA during conjugation and (2) drug-resistance genes that encode the proteins that mediate drug resistance. The bottom half of the figure depicts (from left to right) the genes that encode resistance to tetracycline, streptomycin, penicillin (β-lactamase), chloramphenicol, erythromycin, and gentamicin.
Table1. R-Factor–Mediated Resistance Mechanisms
R factors can carry one or more antibiotic-resistance genes. The medical implication of this is twofold: first, a bacterium containing such a plasmid can be resistant to more than one class of antibiotics (e.g., penicillins and aminoglycosides), and second, the use of an antibiotic that selects for an organism resistant to one antibiotic will select for an organism that is resistant to any antibiotics whose resistance genes are carried by the plasmid. For example, if an organism has the R plasmid depicted in Figure 1, then the use of penicillin will also select for an organism resistant to the other indicated antibiotics because the resistance genes are encoded on the plasmid.
In addition to producing drug resistance, R factors have two important properties: (1) they can replicate independently of the bacterial chromosome because they encode for proteins required for plasmid replication, and as such a cell can contain many copies and (2) they encode for proteins that facilitate plasmid transfer, not only to cells of the same species, but also to other species and genera.
In addition to conveying antibiotic resistance, R factors can confer resistance to metal ions and resistance to certain bacterial viruses by coding for restriction endonucleases that degrade the DNA of the infecting bacteriophages.
Transposon-Mediated Resistance
Transposons are genes that are transferred either within or between larger pieces of DNA such as the bacterial chromo some and plasmids. A typical drug-resistance transposon is composed of three genes flanked on both sides by shorter DNA sequences. The three genes code for (1) transposase, the enzyme that catalyzes excision and reintegration of the transposon; (2) a repressor that regulates synthesis of the transposase; and (3) the drug resistance gene.
