Origins of Resistance

ORIGINS OF RESISTANCE

Some bacteria are said to have innate resistance against antibiotics and this typically reflects variations in the structure of their cell envelope. These will be identified in subsequent sections on resistance mechanisms. Resistance or reduced susceptibility may also be phenotypic, resulting from adaptation to growth within a specific environment. A characteristic of such phenotypic resistance is reversion to antibiotic susceptibility upon subculture in conventional laboratory media and failure to isolate genotypic resistant mutants (section 17). The origins of antibiotic resistance genes are unclear; however, studies using clinical isolates collected before the introduction of antibiotics demonstrated susceptibility, although conjugative plasmids (section 16.1) were present. Resistance can be achieved by horizontal acquisition of resistance genes, mobilized via insertion sequences, transposons and conjugative plasmids, by recombination of foreign DNA into the chromosome, or by mutations in different chromosomal loci. Given that it is only 60 years since the introduction of antibiotics, mutation of common ancestral genes could not be the only resistance mechanism. Many resistance genes will have derived from the diverse gene pool present in environmental microorganisms, most likely produced as protective mechanisms by antibiotic-producing organisms. Genetic exchange is likely to arise in soil and the general environment as well as in the gut of humans and animals. Rapid mutation can occur and there is clearly a heavy selective pressure resulting from the overuse of antibiotics in medical practice. Agricultural and veterinary use of antibiotics also makes an important and unhelpful contribution. The mutation process is not a static event and a complex network of factors influences the rate and type of mutants that can be selected under antibiotic selective pressure. Antibiotic concentration, physiological conditions such as nutrient availability and stress can each regulate mutation rates. The structure of a gene is relevant to mutability. Size is not the main factor, as not every mutation in a gene that encodes an antibiotic target leads to resistance. Resistance only occurs by mutations which are both permissive (i.e. not lethal or leading to an unacceptable reduction in ‘fitness ’ or ability to cause infection) and able to produce a resistance phenotype. The probability that such a mutation arises will be proportional to the number of target sites within the gene. In Escherichia coli, mutations in the gyrA gene, encoding the GyrA subunit of topoisomerase II and leading to fluoroquinolone resistance (section 8) have been identified in at least seven locations, whereas mutational changes in only three positions in the,parC gene, encoding a subunit of topoisomerase IV, have been observed. As a consequence, the prediction that the mutation rate would be higher in,gyrA than parC is correct. Such observations and predictions cannot be extrapolated to other organisms. Indeed, the opposite is true for fluoroquinolone resistance in Strep pneumoniae.