A team of scientists led by Squire Booker at Penn State has discovered a novel strategy by which antibiotic-resistant bacteria change their genetic make-up to evade multiple antibiotics. Image: Penn State Univ. |
For the first time, scientists
have been able to paint a detailed chemical picture of how a particular strain
of bacteria has evolved to become resistant to antibiotics. The research is a
key step toward designing compounds to prevent infections by recently evolved,
drug-resistant “superbugs” that often are found in hospitals, as well
as in the general population. A paper describing the research, by a team led by
Squire Booker, an associate professor in the department of chemistry and the
department of biochemistry and molecular biology at Penn State,
was posted by Science on its
early-online Science Express site. This paper is a continuation of research led
by Booker published in another paper in Science
earlier this month.
The team began by studying a
protein made by a recently evolved “superbug.” Booker explained that,
several years ago, genetic studies had revealed that Staphylococcus sciuri—a non-human bacterial pathogen—had evolved a
new gene called Cfr. The protein created by this gene had been found to play a
key role in one of the bacterium’s mechanisms of antibiotic resistance. Later,
the same gene was found to have crossed over into a strain of Staphylococcus aureus—a very common kind
of bacteria that constitutes part of the flora living in the human nose and on
the skin, and which is now the cause of various antibiotic-resistant
infections. Because this gene often is found within a mobile DNA element, it
can move easily from a non-human pathogen to other species of bacteria that
infect humans.
“The gene, which has been
found in Staphylococcus aureus
isolates in the United States,
Mexico, Brazil, Spain,
Italy, and Ireland, effectively renders the
bacteria resistant to seven classes of antibiotics,” Booker explained.
“Clearly, bacteria with this gene have a distinct evolutionary advantage.
However, until now, the detailed process by which the protein encoded by that
gene affected the genetic makeup of the bacteria was unclear; that is, we
didn’t have a clear 3D picture of what was going on at the molecular
level.”
To solve the chemical mystery of
how such bacteria outsmart so many antibiotics, Booker and his team
investigated how the Cfr protein accomplishes a task called methylation—a
process by which enzymes add a small molecular tag to a particular location on
a nucleotide—a molecule that is the structural unit of RNA and DNA. When this
molecular tag is added by a protein called RlmN, it facilitates the proper
functioning of the bacterial ribosome. Many classes of antibiotics bind to the
ribosome, disrupting its function and thereby killing the bacteria. The Cfr
protein performs an identical function as the RlmN protein, but it adds the
molecular tag at a different location on the same nucleotide. The addition of
the tag blocks binding of antibiotics to the ribosome without disrupting its
function.
“What had perplexed
scientists is that the locations to which RlmN and Cfr add molecular tags are
chemically different from all others to which tags routinely are appended, and
should be resistant to modification by standard chemical methods,” Booker
said. “What we’ve discovered here is so exciting because it represents a
truly new chemical mechanism for methylation. We now have a very clear chemical
picture of a very clever mechanism for antibiotic resistance that some bacteria
have evolved.”
Booker also said he believes the
next step will be to use this new information to design compounds that could
work in conjunction with typical antibiotics.
“Because we know the
specific mechanism by which bacterial cells evade several classes of
antibiotics, we can begin to think about how to disrupt the process so that
standard antibiotics can do their jobs,” he said.
