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Study Links Bacterial Hyper-Recombination and Antibiotic Resistance

NEW YORK (GenomeWeb News) – Pneumococcal bacteria that are capable of hyper-recombination with other bacteria are also more prone to antibiotic resistance, according to a paper published online today in Science.

Researchers from the Imperial College London and Finland's Abo Akademi University used computational approaches to assess multilocus sequence type data on six different genes for about 2,000 pneumococcal genotypes. Their results indicate that pneumococcal strains that are "hyper-recombinant" — predisposed to taking up DNA from other bacteria strains and species — are also the most likely to harbor antibiotic resistance.

"Bacteria have very peculiar sex lives. When humans have kids they mix up their DNA with that of their partner, but bacteria can pick up DNA from all sorts of places, even other species," lead author Bill Hanage, an epidemiologist at the Imperial College London, said in a statement. "Our research shows that bacteria which do this, that is undergo sex with their own and other species, are more likely to develop resistance to antibiotics, protecting them from being killed by these drugs."

Pneumococcal bacteria such as Streptococcus pneumoniae can cause pneumonia, bacterial meningitis, and other diseases, leading to about a million deaths around the world annually. While treatments against pneumococcus are available, many bugs have acquired resistance to standard antibiotics. And the new research suggests this resistance is intimately linked to a pneumococcal strain's overall recombination profile.

"We've known for some time that pneumococcus recombine," Hanage told GenomeWeb Daily News. Now, he said, there's evidence that some do this much more than others — contributing to their antibiotic resistance.

He and his team pulled together multi-locus sequence data on 2,024 different pneumococcus genotypes from the MLST database and homologous sequences characterized in their previous studies. This data represented 1,930 S. pneumoniae genotypes, 40 S. mitis genotypes, 39 S. pseudopneumoniae genotypes, and 15 S. oralis genotypes.

Using a program called Bayesian Analysis of Population Structure, or BAPS, they then placed the genotypes into six clusters based on allele frequencies. Three of the six clusters matched non-pneumococcal bacteria, while three resembled pneumococcal sub-populations.

When the researchers looked for evidence of recombination between the different clusters, they found one cluster — cluster 4 — that contained almost all of the non-pneumococcal alleles.

After integrating cluster information with 3,732 MLST database records on resistance to penicillin, erythromycin, tetracycline, chloramphenicol, and cefotaxime, the researchers detected a significant positive association between cluster 4 and antibiotic resistance. In contrast, cluster 1, which almost exclusively contained alleles from one cluster, negatively associated with resistance.

Based on these results, the researchers speculated that hyper-recombinant pneumococcal strains may generally be more tolerant of foreign DNA — including sequences associated with antibiotic resistance.

"We hypothesize that cluster 4 is an amalgam of strains with a history of hyper-recombination, which leads to them being grouped together by BAPS because they share anomalous DNA sequences," the authors wrote. "By having a history of hyper-recombination, such strains are more likely to accept divergent DNA, both at housekeeping genes and resistance loci, and [are] hence more likely to acquire resistance and housekeeping gene sequences from distantly related pneumococci or other species."

So far the researchers have not detected links between hyper-recombinant pneumococci and other traits with clinical implications, such as increased virulence. "[Hyper-recombinant strains] certainly don't seem to be associated with more aggressive disease, which is comforting," Hanage said.

Nevertheless, Hanage noted, the current approach only provides information about recombination evident in the six genes evaluated by MLST. It's possible that new information will emerge as whole genome sequences become available, he added, along with large-scale or population genomics studies allowing comparisons between many strains.

The team has not yet investigated non-pneumococcal bacteria, Hanage said. But he predicts further research will uncover other bacterial groups in which hyper-recombination and resistance are linked.

Along with statistical studies of some of these other bacterial groups, the researchers plan to investigate the impact of hyper-recombination on evolutionary differences between lineages, if any, Hanage said. They also hope to learn more about how species emerge in bacteria.

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