Researchers analyze how new anti-MRSA abtibiotics function

Jul 28, 2008

A new paper by Shahriar Mobashery, Navari Family Professor in Life Sciences at the University of Notre Dame, and researchers in his lab provides important insights into promising new antibiotics aimed at combating MRSA.

Methicillin-resistant Staphylococcus aureus (MRSA) is a major global health threat that kills approximately 20,000 people in the U.S. alone each year.

Mobashery is a world-renowned expert in antibiotic resistance and enzyme inhibitors and he and his research team have long probed the nuances of MRSA as a superbacterium.

The Notre Dame team investigated two new anti-MRSA â-Lactam antibiotics from the pharmaceutical company Cerexa Inc., which are currently undergoing clinical trails. Both are broad-spectrum antibiotics, but their activities against MRSA and multi-drug-resistant MRSA have been especially noteworthy.

Although current media attention to MRSA may make it seem to be a recent development, the first strain that came to be known as MRSA actually emerged in 1961 in the United Kingdom. This difficult strain of Staphylococcus aureus became a global scourge within a span of a mere few years. Whereas previously Staphylococcus aureus was exquisitely sensitive to â-Lactam antibiotics, a class that includes penicillins (such as methicillin), this variant became resistant to all of the commercially available members of this class of antibiotics. Clinicians had to turn to second lines of antibiotics, which were substantially less effective and often were toxic to the human host.

By the 1980s and 1990s, MRSA had become a serious clinical problem, dreaded by clinicians in health care facilities, prisons and nursing homes. Of late, a new variant of community onset of antibiotic-resistant staph infections emerged outside of institutions.

"For the past 50 or 60 years, we've been able to stay one step ahead of traditional infections," Mobashery said. "However, there are cases of resistance to all eight major existing classes of antibiotics. Actually resistant bacteria are often resistant to multiple classes of antibiotics, not just one or two."

For just over 40 years, scientists have known that bacteria possess a cell wall. Since the health and integrity of the cell wall are critical to the survival of these organisms, it is not surprising that many antibiotics work by either impairing biosynthesis of the cell wall, or simply bind to it to inhibit full structural maturation. In 2006, Mobashery and his team of researchers provided the first clear understanding of the structure of peptidoglycan, the building unit of the bacterial cell wall.

Peptidoglycan, a mesh-like network, is the building block of the bacterial cell wall and neighboring peptidoglycans undergo a so-called "cross-linking" reaction to generate the rigid entity known as the cell wall. Since bacteria cannot regulate their internal pressure, bacterial cells would burst apart and die if cross-linking did not occur.

â-Lactam (e.g., penicillin) and glycopeptide (e.g., vancomycin) antibiotics are designed to impair the bacterial cell wall and inhibit the process of cross-linking, causing bacterial cells to burst and die.

Mobashery and his team have been focusing on a unique protein called penicillin-binding protein 2a (PBP 2a) that MRSA carries on its cell membrane. Previous research has shown that PBP 2a performs the critical cell wall cross-linking reaction.

Mobashery has previously reported that PBP 2a exists in "closed and open" forms. The open form is needed for the physiological functioning of PBP 2a, but the closed form is responsible for the antibiotic resistance manifestations. When the protein interacts with the cell wall at a specific location on its surface, it opens up to carry out the physiological function.

In their latest paper, Mobashery and his team reveal that the new Cerexa antibiotics appear to interact with PBP 2a in a unique way. The antibiotics mimic some of the interactions of the cell wall with PBP 2a, whereby the enzyme is "tricked" to open up as it attempts its physiological function. Once this opening of PBP 2a takes place, its function is inhibited by the novel antibiotics, resulting in bacterial cell death. "Both antibiotics are highly effective in killing MRSA," Mobashery said. "It's a promise that awaits the outcome of the clinical trials."

The paper appears in the July 16 edition of the Journal of the American Chemical Society.

Source: University of Notre Dame

Explore further: Lifeline extended for critically endangered porpoise

add to favorites email to friend print save as pdf

Related Stories

Discovery in the fight against antibiotic-resistant bacteria

Dec 18, 2014

For four years, researchers at Universite catholique de Louvain have been trying to find out how bacteria can withstand antibiotics, so as to be able to attack them more effectively. These researchers now understand how one ...

New antibiotic in mushroom that grows on horse dung

Nov 07, 2014

Researchers from the Institute of Microbiology at ETH Zurich have discovered a new protein with antibiotic properties in a mushroom that grows on horse dung. Researchers are now exploring the various potential ...

Recommended for you

Lifeline extended for critically endangered porpoise

41 minutes ago

Mexico's recent decision to buy-out gillnet fisheries in the upper Gulf of California may give one of the world's rarest species the breathing space it needs to survive. Time is still ticking, but the move ...

New 'enigma' moth helps crack evolution's code

1 hour ago

Aenigmatinea glatzella – which has iridescent gold and purple wings – is a 'living dinosaur' that represents an entirely new family of primitive moths. This is the first time since the 1970s that a new ...

Hundreds of starving koalas killed in Australia

4 hours ago

Close to 700 koalas have been killed off by authorities in southeastern Australia because overpopulation led to the animals starving, an official said Wednesday, sparking claims of mismanagement.

Bridge jumper says sea lion saved him

4 hours ago

A man who jumped off San Francisco's Golden Gate Bridge to try to take his own life and was kept afloat by a sea lion said Wednesday suicide prevention was now his life's work.

Brazil receives macaw pair from Germany

4 hours ago

A pair of endangered blue macaws of the kind made famous by the hit animated "Rio" movies arrived in Brazil from Germany on Tuesday as part of a drive to ensure the bird's survival.

User comments : 0

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.