Staph infections are common in the hospital setting and in the community, but the strains that are prevalent in these two environments differ somewhat. In their study in mBio this week, a group in Denmark looked at one of these differences and found that pressure from antibiotic use in the hospital is driving some unexpected evolutionary changes in Staphylococcus aureus that essentially making it leaner and meaner.
Staph is a huge problem in hospitals, particularly in intensive care units, where it is the most frequently isolated pathogen. Depending on whom you ask, between 15 and 60% of these isolates are agr defective, meaning they lack the primary quorum-sensing-controlled virulence regulatory system, making them defective in sensing one another and mounting a timed quorum-sensing driven attack on the body. Lacking quorum sensing would seem, on the face of it, to be a good thing for the host, and it has been identified as a central player in Staph virulence with respect to septic arthritis, skin abscesses, and other infections. Agr-defective strains are less virulent than the wild type in all these cases, and the agr locus works fine in virually all community-acquired Staph strains.
The fact remains that in the hospital a large proportion of Staph isolates are agr-defective. What’s more, agr-defective strains in nosocomial infections are associated with increased mortality and with greater probability of resistance to glycopeptide antibiotics. Paulander et al. explored the reasons behind this seeming paradox: why does losing a seemingly necessary virulence factor make Staph more dangerous in the hospital setting?
They focused their study on the fitness costs of carrying around a cumbersome quoroum sensing system and whether those costs were amplified in the presence of antibiotics, a factor that doesn’t often figure in community-acquired Staph infections but represents a significant evolutionary pressure in the hospital environment.
Using head-to-head growth competition experiments, the authors showed that agr-defective strains are more fit than the wild type in the presence of sublethal concentrations of ciprofloxacin, mupirocin, and rifampin but not vancomycin.
Lead author on the study, Hanne Ingmer, says quorum sensing, while useful to Staph in many situations, appears to be dispensible. “Quorum sensing has a fitness cost because once the system is induced it initiates the expression of a lot of virulence factors that are "costly" for the cell to produce. Apparently for some types of infections or infection stages the quorum sensing controlled gene products are not needed and so there is a strong selection for the negative variants under those conditions,” says Ingmer.
Ingmer and her colleagues specifically linked the fitness costs to the expression of one component of the agr quorum sensing system in particular: the intracellular effector molecule RNAIII. By inducing the costly expression of RNAIII, exposure to low levels of ciprofloxacin, mupirocin, and rifampin increases the fitness cost of carrying a functional agr quorum sensing system. The results indicate that the presence of low levels of certain antibiotics, a condition often found in the bodies of hospital patients, makes the quorum sensing system a costly piece of baggage for Staph, a fact that could explain why hospital-acquired infections are so frequently associated with arg-defective strains. Treatment with those antibiotics will select for agr-deficient mutants, says Ingmer, and this should be taken into account when designing antimicrobial chemotherapy for hospitalized patients.
“Since we show that some antibiotics select for quorum sensing negative S. aureus and others have shown that such variants are more prone to become vancomycin resistant, clinicians should really consider any prior antibiotic treatments before relying on vancomycin as a last resort antibiotic,” Ingmer says.