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Sequencing Study Offers Clues to Resistance Patterns in Pneumococcal Bacteria

By Andrea Anderson

NEW YORK (GenomeWeb News) – An international research team reported online today in Science that it has used whole-genome sequencing and phylogenetics to look at how a bacterial pathogen has evolved to skirt existing treatments and vaccines.

Researchers from the Wellcome Trust Sanger Institute and elsewhere sequenced hundreds of isolates from a drug-resistant lineage of Streptococcus pneumoniae — a bacterial species that can cause pneumonia, meningitis, and other diseases. Using this sequence data, the team was able to characterize the extent to which substitutions, recombination, and horizontal gene transfer have helped the bug evade vaccine and drug treatments.

"We knew that recombination occurred in this organism. What we didn't know so much about before, though, was the actual size of the regions that were being recombined," senior author Stephen Bentley, a researcher with the Wellcome Trust Sanger Institute, told GenomeWeb Daily News. "So we now have a much clearer picture of how much recombination contributes to variation in the genome — and that's a significant amount."

Bentley and his colleagues used the Illumina Genome Analyzer to sequence 240 multi-drug resistant isolates from a pandemic clone lineage known as Pneumococcal Molecular Epidemiology Network clone 1, or PMEN1, that was first detected in Barcelona in the mid-1980s and has since spread around the world.

"There are a number of clones which have been designated as being pandemic clones associated with antimicrobial resistance," Bentley said. "Because they're resistant, they're of great interest to clinicians. And because they're spreading so rapidly, that's of interest as well, because that implies that they transmit very easily between humans."

The isolates, which had a range of drug-resistance profiles, were collected from 1984 to 2008, the researchers explained, and included strains collected in seven European countries, six countries in the Americas, eight Asian countries, and South Africa.

A prior sequencing study focusing on one isolate from the PMEN1 lineage uncovered an integrative and conjugative element that confers resistance to the antibiotics chloramphenicol and tetracycline, the researchers noted. But not every pneumococcal strain that survives treatment with these and other drugs has the same ability to spread between humans.

"There are obviously other genetic factors at play here which determine whether a clone can spread," Bentley said.

After mapping the newly sequenced strains to an S. pneumoniae reference chromosome, the researchers identified 57,736 SNPs — variants that they subsequently used to create a phylogeny for the PMEN1 bugs. They also detected 1,032 small insertions and deletions that were largely concentrated in non-protein-coding bits of the genome.

Moreover, their analyses turned up evidence of extensive recombination in the PMEN1 lineage.

Some 88 percent of SNPs detected stemmed from 702 recombination events, the researchers reported. And when they looked across the genome as a whole, they found that nearly three-quarters of the reference sequence showed evidence of recombination in at least one of the isolates tested.

Horizontal gene transfer events appear to be particularly common in certain parts of the S. pneumoniae genome, including regions coding for antigens detected by the human immune system.

Based on clustering patterns in the phylogenetic tree, the team was also able to get insights into when and how resistance to antibiotics and vaccines emerge in different parts of the world. Their findings suggest that the drug-resistant PMEN1 lineage first appeared in Spain around 1970. From there, the clone spread to other parts of Europe before popping up in Asia and the Americas on several occasions.

"You could try to track the spread of a clone just by the dates that they're first actually detected in a particular country," Bentley said. "But by overlaying that information onto the phylogeny, we can quite clearly track the direction of transmission."

Because isolates turning up in different parts of the world at different times seem to have independently developed certain antibiotic resistance mechanisms, the researchers noted, it appears that selective pressure exercised by antibiotics has led to convergent adaptations in S. pneumoniae.

Given the nature and extent of the changes detected within the PMEN1 isolates, the researchers argue that genetic profiling and sequencing may be increasingly important for tracking bacterial pathogens and getting insights into genotype, virulence, and resistance profiles of a given strain.

"I think in the not-too-distant future, genome sequencing will become very important in surveillance of bacterial pathogen populations," Bentley said. "Whole-genome sequencing costs are coming down so rapidly that it's going to become feasible to do whole-genome sequencing as a routine approach."

Bentley and his team are now looking at several other drug resistant S. pneumoniae clones in an effort to learn more about the evolution of such resistance mechanisms in the species as a whole. "We can predict that they're not going to all behave in the same way in terms of mutation rates and recombination rates," Bentley said.

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