Why is it that only one strain of MRSA has ever managed to pick up resistance to vancomycin? That's the question asked by the authors of a study in mBio this week. Using comparative genomics, they uncovered what makes the MRSA strain CC5 so proficient at picking up resistance genes and how it is suited to succeed in the hospital setting.
MRSA a Growing Problem
Infection with methicillin-resistant Staphylococcus aureus, or MRSA, is now among the top 22 leading causes of death in the U.S., and vancomycin is a crucial drug for treating these infections. But since 2002, one particular type of MRSA strain, called clonal cluster 5 (CC5), has periodically acquired resistance to vancomycin, a situation that can turn a bad infection into a deadly one.
The type of MRSA has managed to acquire resistance to vancomycin on 12 separate occasions, and although it hasn't spread widely yet, the risk that MRSA could eventually overwhelm even our last-line drugs is a very serious one. Researchers at Harvard, the Massachusetts Eye and Ear Infirmary in Boston and the Broad Institute in Cambridge and other institutions sequenced the genomes of all available vancomycin resistant MRSA strains to find what distinguishes them from other lineages and why CC5 is apparently more adept than other strains at picking up vancomycin resistance.
Why does CC5 acquire resistance while other MRSA strains don't?
Kos et al. report that vancomycin-resistant MRSA strains and other CC5 lineages have some important differences from other types of MRSA, including adaptations that allow them to co-exist with other types of bacteria and may help them take up foreign DNA. They all lack the operon called bsa, for instance, a set of genes that encode a lantibiotic bacteriocin, an antibiotic protein made by bacteria to kill other bacteria. This is missing operon is significant, say the authors, because it enables CC5 to get along well with other bacteria in mixed infections. Instead of killing off competing organisms, CC5 aims to co-exist. This enables it to pick up genes - like the one that encodes vancomycin resistance - from unexpected places. Mixed infections are breeding grounds for antibiotic resistance because they encourage the exchange of genes among very different kinds of organisms.
In roughly the place where these bacteriocin genes are missing is a unique cluster of genes that encode enterotoxins, proteins that attack the human host and, again, could make it easier for mixed populations of bacteria to grow at infection sites. Finally, CC5 has a mutation in a gene called dprA, which is known to influence the ability to assimilate foreign DNA. The mutation could alter or eliminate the function of dprA in CC5 strains of MRSA, making it amenable to taking up DNA from outside sources.
The sum of all these traits, including the lack of bacteriocin production, the ability to produce enterotoxins, and mutations in the ability to assimilate foreign DNA, is a lineage of S. aureus that is optimized to grow in exactly the types of multi-species infections where gene transfer could occur.
This makes CC5 well adapted to succeed in hospitals by acquiring new resistances, where pathogens are under continuous pressure from antibiotics to survive and evolve. Frequent use of antibiotics in hospital patients could select for strains like CC5 that have an enhanced ability to co-exist with bacteria that provide genes for antibiotic resistance.