Genomes Reveal How MRSA Bacteria Gain Resistance to Last-Line Drugs

Researchers have determined and compared the genome sequences of MRSA strains now also resistant to vancomycin, a key last-line antibiotic for severe MRSA infections. The new information enabled the scientists to trace the origin and development of vancomycin resistance in these strains.


Since 2002, there have been 12 documented cases of vancomycin-resistant Staphylococcus aureus (VRSA) infection in the United States - all strains of Methicillin-resistant S. aureus (MRSA) clonal cluster 5 (CC5), the predominant lineage responsible for US hospital-acquired MRSA infections. Most of the VRSA cases arose in diabetic patients with limb wounds infected by multiple bacterial species, including vancomycin-resistant Enterococcus (VRE). Sequence comparisons in the current study showed unambiguously that each strain independently acquired transposon Tn1546, likely from the co-infecting VRE.

The team also identified shared features that may have helped acquire the vancomycin resistance and evade human immune defenses. "The genome sequence gave us unprecedented insight into what makes these highly resistant bacteria tick. Several things were remarkable," says team leader, Harvard’s Michael Gilmore, PhD; "Vancomycin resistance repeatedly went into just one tribe of MRSA, so the question became 'what makes that group special -- why did they start getting vancomycin resistance?"' First author Veronica Kos, PhD and senior research associate in Gilmore’s laboratory at Harvard’s Massachusetts Eye and Ear Infirmary (Boston, MA, USA) added, "What we found was that this group of MRSA has properties that appear to make it more social, so they can live with other bacteria like Enterococcus. This would allow those MRSA to more easily pick up new resistances. The good news is that some of these properties weaken the strain's ability to colonize, and may be limiting their spread."

VRSA and other CC5 strains were found to possess traits that appear to be advantageous for proliferation in mixed infections. They harbor a cluster of unique superantigens and lipoproteins that confound host immunity and so allow the bacteria to flourish, increasing the odds that resistance factors will be transferred in a mixed infection. A frameshift identified in the dprA gene may also have made this lineage conducive to the transposon acquisition. The genomes also provided clues as to why person-to-person spread of VRSA has not become common. Strains in the CC5 clade lack a bacteriocin operon, a disadvantage in any encounter with other naturally occurring staph strains that normally live on the skin and that do produce this factor.

The research, reported on May 22, 2012, in the journal mBio, was conducted through the Harvard-wide Antibiotic Resistance Program, funded by the National Institute of Allergy and Infectious Diseases (NIAID; Bethesda, MD, USA). Scientists of the program, in partnership with others, are using information from this and related studies to develop new ways to help prevent and treat infection by MRSA, VRSA, and VRE. They have identified several new compounds that stop MRSA by hitting new targets, and are currently subjecting these to further tests.

Related Links:
Massachusetts Eye and Ear Infirmary
NIH/National Institute of Allergy and Infectious Diseases