For nearly half a century, 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 its full structural maturation.
Now, a new research study led by University of Notre Dame chemist Shahriar Mobashery has provided, for the first time, a clear understanding of the structure of peptidoglycan, the building unit of the cell wall. This knowledge has led to a three-dimensional depiction of the cell wall structure itself, which has, in turn, contributed to an understanding of how certain antibiotics interfere with the functioning of the cell wall.
Roughly 50 years ago, scientists determined that the cell wall of bacteria consists of peptidoglycan, a mesh-like network. Peptidoglycan is the building block of the bacterial cell wall and neighboring peptidoglycans undergo a so-calledcross-linkingreaction 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.
Although scientists recognized the critical role peptidogylcan plays in the bacterial cell wall, they have been unable to determine its exact three-dimensional structure.
Samples of peptidogylcan did not exist in either sufficient purity or quantity for researchers to be able to describe its structure and that of the bacterial cell wall,said Mobashery, the Navari Family Professor of Life Sciences.
Mobashery and his team were able to finally characterize the framework of peptidoglycan by developing, through a painstaking 37-step procedure, a synthetic fragment of the cell wall in a lab. And, through extensive studies of the fragment, the researchers were able to characterize the structure of the cell wall.
The breakthrough reveals what the cell wall looks like and provides insights into how ß-lactam (e.g., penicillin) and glycopeptide (e.g., vancomycin) antibiotics are able to impair the bacterial cell wall.
For the first time, we can visualize how this entity that is critical for the survival of bacteria looks and operates,Mobashery said.And, as the old saying goes, a picture is as good as a thousands words.
Antibiotics of the penicillin class, for example, inhibit the process of cross-linking, causing bacterial cells to burst and die. Vancomycin and glycopeptide antibiotics bind to the cell wall and prevent its cross-linking.
Scientists have known how penicillin inhibits a specific enzyme in the biosynthesis of the bacterial cell wall,Mobashery said.Vancomycin, which many describe as the drug of last resort for certain hard-to-treat bacterial infections, works differently. So it is clearly important to know how both of these antibiotics work in disrupting the function of peptidoglycan in maintaining the integrity of the cell wall.
Mobasherys discovery comes at a critical time because antibiotic resistance has become a major public health problem. Inappropriate use of antibiotics has increased this phenomenon. Roughly 40 percent of children who see a doctor for a common viral cold are prescribed antibiotics, even though antibiotics are not effective for such viruses, a disconcerting practice that ironically leads to emergence of antibiotic-resistant bacteria.
In treatment of bona fide bacterial infections, many patients, feeling better after a day or two of antibiotics, fail to follow a full course of treatment. Taking the drug when it is not appropriate or not taking it in the proscribed manner provides fertile grounds for resistance.
In 2004, theAmericanAcademyof Pediatrics and theAmericanAcademyof Family Practice began recommending that doctors avoid prescribing antibiotics for ear infections in children. The groups believe that if they can reduce antibiotics use for such infections, they can stop the rise of antibiotic-resistant germs.
Mobashery and his team believe that their characterization of the chemical architecture of the cell wall will help pave the way for much-needed newer classes of antibiotics.
For the past 50 or 60 years, weve 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.
Members of the Mobashery team were Dusan Hesek, Samy Meroueh, Mijoon Lee and Jed Fisher from Notre Dame and Krisztina Bencze and Timothy Stemmler ofWayneStateUniversity.
Their findings were published in a recent edition of the Proceedings of the National Academy of Sciences.
* Contact: * _Shahriar Mobashery, Navari Family Professor of Life Sciences, 574-631-2933, mobashery@nd.edu
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