Featured Research

from universities, journals, and other organizations

New Model Of Staph Drug Resistance Implicates Unlikely Protein; Findings May Lead To New Drugs That Overcome Resistance

Date:
August 22, 2001
Source:
Rockefeller University
Summary:
Researchers at The Rockefeller University have established a new model to explain how the infectious "staph" bacterium evades several widely used antibiotics. They show that a protein previously thought to play no role in drug resistance in Staphylococcus aureus is, in fact, essential.

Researchers at The Rockefeller University have established a new model to explain how the infectious "staph" bacterium evades several widely used antibiotics. They show that a protein previously thought to play no role in drug resistance in Staphylococcus aureus is, in fact, essential.

The new study, which is co-authored by Mariana Pinho, Hermínia de Lencastre, Ph.D, and Alexander Tomasz, Ph.D., and appears in the August 21 online edition of the Proceedings of the National Academy of Sciences, emphasizes the importance of looking for new antibiotics that target this protein.

"Mariana's work shows that the old model of drug resistance in staphylococci is no longer tenable," says Tomasz, principal investigator of the research and professor at Rockefeller.

Since the introduction of antibiotics in the 1940s, Staphylococcus aureus, the number one cause of potentially life-threatening hospital-borne infections, has developed several mechanisms to beat the potentially lethal effects of chemotherapeutic agents. Of these bacterial tricks, the most important was the acquisition of a foreign gene - the mecA gene - that confers resistance to methicillin in addition to penicillin and a host of other antibiotics, all belonging to what scientists refer to as the beta-lactam class of antibiotics.

Today, almost half of all staphylococcal infections in U.S. hospitals are caused by these methicillin-resistant S. aureus (MRSA) strains. By studying the bacteria's resistance mechanisms at the molecular level, researchers in the Laboratory of Microbiology at Rockefeller, working with researchers in the Laboratory of Molecular Genetics at the Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Portugal, hope to come up with new strategies for fighting such resilient microbes.

The beta-lactam class of antibiotics kills bacteria by binding to and inactivating proteins, called penicillin-binding proteins (PBP), that help build the bacterial cell wall. Without a proper cell wall, the bacteria essentially cannot hold themselves together and burst. However, MRSA strains are impervious to antibiotics because the acquired mecA gene codes for a slightly different PBP - PBP2A - which is not destroyed by beta-lactam antibiotics. Formerly, scientists believed that this foreign PBP conferred drug resistance by completely taking over the role of its native counterparts in cell wall synthesis, thereby allowing the bacteria to survive despite the presence of antibiotics.

But a major study led by de Lencastre in 1994 punched a hole in this model of beta-lactam resistance: she and Tomasz showed that a large number of other proteins native to staphylococci, termed auxiliary proteins, were also necessary for PBP2A to work. Using genetic techniques to sort out these proteins, Pinho discovered that one of them was PBP2. The observation was perplexing: how could a protein exquisitely sensitive to beta-lactam antibiotics be involved in resistance against these drugs?

Now, the researchers have identified the solution to this riddle. They show that the acquired PBP2A in MRSA strains cooperates with a specific region of the native PBP2 to build cell walls in the presence of beta-lactam antibiotics.

"This is the first time we have seen an imported protein learn to cooperate with a native protein," says Tomasz.

Furthermore, the researchers demonstrate that the two proteins functionally complement each other in cell wall synthesis. PBPs tend to exhibit two separate functions when building the cross-hatched network of cell walls - linking sugars and linking short protein pieces called peptides. The recent work finds that the acquired PBP2A serves to link peptides while the native PBP2 links sugars.

This explains why it is possible for PBP2 to aid in resistance while still being inactivated by the antibiotic. Beta-lactam antibiotics are known to inactivate PBPs by binding to the peptide-linking region of the protein, hence the sugar-linking region remains free to cooperate in the resistance mechanism.

The findings indicate that the sugar-linking region or domain of PBP2 is a good target for new antibiotics. Drugs designed to block this activity could be used in combination with beta-lactam antibiotics to disable resistance mechanisms and successfully kill the staphylococci bacteria.

"Our results immediately suggest a drug target that until now has gone largely unexplored," says Pinho.

The emergence of antibiotic resistance in infectious microbes throughout the world is a serious public health threat. According to a recent report by the World Health Organization, "Drug-resistant infections in rich and developing nations alike are threatening to make once treatable diseases incurable." The development of new antibiotics along with the modification of old ones is of utmost importance.

###

This paper is available online at the Proceedings of the National Academy of Sciences Web site: http://www.pnas.org.

The research was funded by a grant from the National Institutes of Health to Tomasz and by a grant from the Fundação para a Ciência e Tecnologia (FCT), Ministry of Science and Technology, Lisbon, Portugal to de Lencastre.

Tomasz is the Plutarch Papamarkou Professor of Microbiology and Infectious Diseases at The Rockefeller University. Pinho is a visiting scientist at Rockefeller from the Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, and Hermínia de Lencastre is a senior research associate at Rockefeller and head of the Laboratory of Molecular Genetics at the Instituto de Tecnologia Química e Biológica.

John D. Rockefeller founded Rockefeller University in 1901 as The Rockefeller Institute for Medical Research. Rockefeller scientists have made significant achievements, including the discovery that DNA is the carrier of genetic information. The University has ties to 21 Nobel laureates, six of whom are on campus. Rockefeller University scientists have received the award in two consecutive years: neurobiologist Paul Greengard, Ph.D., in 2000 and cell biologist Günter Blobel, M.D., Ph.D., in 1999, both in physiology or medicine. At present, 33 faculty are elected members of the U.S. National Academy of Sciences, including the president, Arnold J. Levine, Ph.D. Celebrating its centennial anniversary in 2001, Rockefeller the nation's first biomedical research center continues to lead the field in both scientific inquiry and the development of tomorrow's scientists.


Story Source:

The above story is based on materials provided by Rockefeller University. Note: Materials may be edited for content and length.


Cite This Page:

Rockefeller University. "New Model Of Staph Drug Resistance Implicates Unlikely Protein; Findings May Lead To New Drugs That Overcome Resistance." ScienceDaily. ScienceDaily, 22 August 2001. <www.sciencedaily.com/releases/2001/08/010822081224.htm>.
Rockefeller University. (2001, August 22). New Model Of Staph Drug Resistance Implicates Unlikely Protein; Findings May Lead To New Drugs That Overcome Resistance. ScienceDaily. Retrieved July 24, 2014 from www.sciencedaily.com/releases/2001/08/010822081224.htm
Rockefeller University. "New Model Of Staph Drug Resistance Implicates Unlikely Protein; Findings May Lead To New Drugs That Overcome Resistance." ScienceDaily. www.sciencedaily.com/releases/2001/08/010822081224.htm (accessed July 24, 2014).

Share This




More Plants & Animals News

Thursday, July 24, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Stone Fruit Listeria Scare Causes Sweeping Recall

Stone Fruit Listeria Scare Causes Sweeping Recall

Newsy (July 22, 2014) — The Wawona Packing Company has issued a voluntary recall on the stone fruit it distributes due to a possible Listeria outbreak. Video provided by Newsy
Powered by NewsLook.com
Michigan Plant's Goal: Flower and Die

Michigan Plant's Goal: Flower and Die

AP (July 22, 2014) — An 80-year-old agave plant, which is blooming for the first and only time at a University of Michigan conservatory, will die when it's done (July 22) Video provided by AP
Powered by NewsLook.com
Huge Schizophrenia Study Finds Dozens Of New Genetic Causes

Huge Schizophrenia Study Finds Dozens Of New Genetic Causes

Newsy (July 22, 2014) — The 83 new genetic markers could open dozens of new avenues for schizophrenia treatment research. Video provided by Newsy
Powered by NewsLook.com
CDC Head Concerned About a Post-Antibiotic Era

CDC Head Concerned About a Post-Antibiotic Era

AP (July 22, 2014) — Sounding alarms about the growing threat of antibiotic resistance, CDC Director Tom Frieden warned Tuesday if the global community does not confront the problem soon, the world will be living in a devastating post-antibiotic era. (July 22) Video provided by AP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
 
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:  

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:  

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile iPhone Android Web
Follow Facebook Twitter Google+
Subscribe RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins