In the Blink of an Eye: Mutating Escherichia Coli and Salmonella
Abstract & Commentary
Synopsis: A recent study demonstrates the high mutation frequencies of some bacteria.
Source: LeClerc J E, et al. High mutation frequencies among Escherichia coli and Salmonella pathogens. Science 1996; 274:1208-1211.
Genetic change occurs through nucleotide mutation or through horizontal transfer of exogenous nucleotide sequences. Genes like those that govern antimicrobial resistance are thought to arise primarily through the latter mechanism. Plasmids are extrachromosomal pieces of DNA that facilitate horizontal movements of genes, and plasmid-mediated antibiotic resistance is thought to be the prime mover of the global spread of antimicrobial resistance. Plasmids are certainly an important factor in the spread of resistance, but one issue that is not resolved is the role of mutations in the chromosome of common bacteria, pathogenic or otherwise, that create essentially new strains to fill a pathogenic niche. Chromosomes are protected against facile mutation by genes that coordinate methyl-directed mismatch repair (MMR). Strains deficient in MMR mutate more rapidly.
These workers at the FDA wanted to know how quickly common organisms like Escherichia coli and Salmonella enterica mutate. They screened the FDA collection (what a group of pathogens that must be!) for their ease of mutation for rifampicin susceptibility. They found 26 strains hypermutable to rifampicin; nine of these 26 displayed a high frequency of mutation to additional antimicrobials. These strains, accounting for only 2.6% of all strains screened, contained what is called a high mutator and were characterized by a defect in MMR. Four proteins called MutH, MutL, MutS, and UvrD (or MutU) are essential for mismatch correction. As it turned out, using plasmid genes to reconstitute one of the four proteins, MutS was the most commonly lacking protein.
The mutator strain was next shown to have a deletion downstream from the MutS gene, and this type of mutation, argue the authors, allows for promiscuous recombination in mutator strains. Promiscuity, in fact, may drive this kind of selection. It is the very nature of the mutator strain that favors its survival in a hostile environment, one in which many foreign genes may be available for insertion into the chromosome.
COMMENT BY JOSEPH F. JOHN, MD
Simplicity wins the day here. The experimental question was simple: Do enteric pathogenic bacteria have an advantage through mutation to rapidly incorporate survival genes? The answer lies in a stockpile of pathogenic enteric bacteria at the FDA waiting for some crafty investigators to show the configuration of their genomes. The finding was startling, indeed, that bacteria even with known pathogenic mechanisms are further positioned via facile means of taking on new DNA into their chromosomes to expand their survival mechanisms. We in epidemiology have been fixated on identifying plasmid-mediated resistance traits since the argument has been that those strains most likely transfer their resistance genes to susceptible neighbors. This does happen, though the present study suggests that single resistance genes may end up on plasmid or chromosomal sites after hypermutable loci evolved.
This resistance story is starting to make more sense (i.e., background of sequence specificity), in this case, a stretch of DNA that lacks repair genes, that by nature of its mutator predisposition and exposure to other new genes virtually bounces through its tumultuous life in search of new life through new genes. These new genes may be in the form of antimicrobial resistance genes, virulence genes, or survival genes like those that regulate osmolar pressures.
The clinical importance amidst all these molecular shenanigans is to recognize that hypermutator bacteria may be a huge threat in an environment like a hospital where there are so many facilitator genes available. Strategies to limit the emergence of these types of strains may become part of infection control in time just like our move to eliminate resistance-plasmid containing nosocomial bacteria.
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