mBiosphere

MRSA resistant to last-line antibiotic is well-suited to success in hospitals

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.

Kissing cousins C. neoformans and C. gattii cause different types of disease. Why? The answer may lie in how the host responds to infection

Cryptococcus gattii and C. neoformans are very closely related fungi, but when it comes to the infections they cause there are some important differences. In their study in mBio this week, Ngamskulrungroj et al. drilled down into those differences using a mouse model and found that C. gatii may be a bigger problem for the lungs because it suppresses the immune response there.

Between them, C. gattii and C. neoformans are the most common fungal pathogens that cause fatal central nervous system infections in humans. But they don't necessarily target the same groups of people: C. neoformans is classified as an AIDS-defining opportunistic pathogen, while C. gattii is classified as a primary pathogen. What's more, C. gatii appears to specialize in lung infections. Only 35% of C. neoformans patients suffer from a lung infection, while 70% of C. gattii patients do.

In their study, Ngamskulrungroj et al. infected mice intravenously or through the respiratory route with various strains of C. gattii and C. neoformans. When infected through their lungs, C. neoformans killed mice through a brain infection and C. gattii killed them through a lung infection, showing that C. gattii probably cannot cause fulminant (sudden) meningoencephalitis when infected through the lungs. This suggested to the authors that the lungs mount a stronger protective immune response to C. gattii than to C. neoformans, preventing C. gattii from getting into the bloodstream and the brain. They also observed that C. gattii was superior to C. neoformans at growing within the lungs, reaffirming what is commonly observed in patients: C. neoformans to the brain, C. gattii to the lungs.

Treating tumors with anthrax toxin?

Could anthrax toxin be used to treat tumors? Yes, according to the authors of a study in mBio this week. They altered anthrax toxin to deliver it's potent cargo only to cells that carry a type of receptors that are enriched on several types of tumors. The altered anthrax toxin effectively attached, deposited pore-making proteins in the cell, and shuttled toxic enzymes through the newly made pores.

As we all learned back in 2001, anthrax is not something you'd want to sprinkle on your breakfast cereal. Its toxin is composed of three parts: the lethal factor, the edema factor, and the protective antigen. The protective antigen binds to surface receptors on human cells and creates pores that fold and transport lethal factor and edema factor enzymes into the cell. Once inside, these effector proteins unfold and go about their business of modifying their various targets.

An adaptable 'vehicle'

Mechaly et al. treated the anthrax protective antigen as an adaptable vehicle for delivering proteins into the cytosolic compartment of human cells. They mutated two residues within the protective antigen and fused each of two different receptor-binding proteins to the mutated protein. The resulting fusion proteins, one that binds human epidermal growth factor and one that binds diptheria-toxin receptors, effectively delivered their payloads of lethal factors and edema factors to targeted cells and not to cells that lacked the appropriate receptors.

Interestingly, the receptor for human epidermal growth factor, here targeted for toxin delivery, is enriched on several types of tumors, making the protective antigen- epidermal growth factor a potential treatment option. According to the authors, other ligands whose receptors are enriched on the target cells of choice would also be candidates for fusion to anthrax toxin.

Commentary: Black Queen Hypothesis sheds light on evolution of complexity

In mBio this week, authors Joel Sachs and A.C. Hollowell of the University of California Riverside comment on "The Black Queen Hypothesis: Evolution of Dependencies through Adaptive Gene Loss" , a paper that created a bit of a stir when it was published earlier this month. Sachs and Hollowell write that the hypothesis has implications for how we understand the evolution of bacterial genomes and for the development of new techniques for growing bacteria in the lab. It also helps us understand how complex consortia of microorganisms are created and how they continue to work even when it appears some participants act against their own best interests.

The Black Queen Hypothesis, as described by the authors J. Jeffrey Morris, Richard Lenski, and Erik Zinser, describes the idea that microorganisms can lose the ability to carry out certain "leaky" functions if they can benefit from another organism to do it for them. It gives a name and a shape to the idea that cooperation among microbial species can be automatic and based upon purely selfish traits. The name comes from the card game Hearts, in which players generally try to avoid holding the queen of spades, the black queen. According to the hypothesis, the microbe unlucky enough to be providing a commodity or a service that is "leaky" and can be enjoyed by others in the vicinity, is holding the black queen - carrying the burden of producing for others while not necessarily getting much in return.

According to Sachs and Hollowell, one of the more helpful aspects of the hypothesis is that it helps us to understand what we see around us everywhere: microbial communities marked by disentangleable networks of interactions. The theory meshes nicely, they say, with models of by-product mutualism or by-product reciprocity, which predict that natural selection will shape receivers of by-products to maximize these benefits by being cooperative to by-product producers. Hence, they say, the trade-off in which one organism loses a gene and gains benefits from a "leaky" producer don't end there: it is in the benefitting organism's interest to give back, maximizing its benefits by being cooperative with the producers. Thus, the predicted evolutionary steps are as follows: (i) selfish usage of another species’ products, (ii) genome streamlining to minimize production of resources that can be gotten from others, and finally (iii) the evolution of costly cooperative traits to maximize vital functions produced by others. It's easy to see how gives and takes like this could quickly lead to a group of interacting partners who cannot be extricated from their surroundings and grown in the lab environment.