Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers Determine How "Hospital Staph" Resists Antibiotics

22.10.2002


Structural studies of a key enzyme have revealed how dangerous strains of the bacterium, Staphylococcus aureus, become resistant to antibiotics.



Resistant strains of Staphylococcus aureus, which are also called "hospital staph" because of their prevalence in hospitals, constitute 34 percent of the clinical isolates in the United States, more than 60 percent in Japan, Singapore and Taiwan, and more than 50 percent in Italy and Portugal. And the emergence of strains of Staphylococcus that are resistant to vancomycin — the antibiotic of last resort — makes public health concerns about drug- resistant strains of the bacterium even more urgent.

In an article published online on October 21, 2002, in the journal Nature Structural Biology, Daniel Lim and Natalie Strynadka, who is a Howard Hughes Medical Institute international research scholar, reported structural studies of the enzyme known as penicillin-binding protein 2A (PBP2a). Lim and Strynadka are at the University of British Columbia.


Before the advent of drug-resistant strains of Staphylococcus aureus, staph infections were treated using beta-lactam antibiotics such as methicillin, which block the bacterial enzyme PBP. This enzyme — called a transpeptidase — normally catalyzes the cross-linking of structural molecules in the bacterial cell wall. Blocking PBP with methicillin weakens the cell wall, which ultimately bursts, killing the bacterium.

However, a methicillin-resistant strain of the bacteria has evolved that has acquired the gene for a new version of PBP — PBP2a —from another bacterium. The challenge, as well as the opportunity, said Strynadka, is to understand why PBP2a is resistant to beta-lactam antibiotics.

"What is very attractive from a therapeutic point of view is that PBP2a constitutes a single target, in terms of developing new antibiotics that can overcome this resistance," she said.

To understand the detailed structure of PBP2a, Lim produced a version of the enzyme that lacked a segment that anchored it to the cell membrane, but which retained the enzyme’s catalytic activity. Eliminating the anchoring segment rendered the protein soluble, so that the researchers could crystallize the protein for use in x-ray crystallography studies. In x-ray crystallography, researchers direct an x-ray beam through crystals of a protein to deduce its structure by analyzing the pattern of diffraction that is produced. Analysis by Lim and Strynadka revealed critical differences between the structures of PBP2a and other beta-lactam antibiotic sensitive PBPs.

"By comparing the native enzyme with previously known structures of transpeptidases, we came to understand that PBP2a had evolved distortions of the active site that prevent an effective reaction with the antibiotic," said Strynadka. An enzyme’s active site is the pocket within which the enzyme carries out its catalytic reaction. In the case of PBP2a, this catalytic reaction drives the essential cross-linking of cell-wall proteins in the bacterium.

"Although beta-lactam-sensitive bacteria still have a number of these normal transpeptidases, they also have PBP2a, which because of its distorted active site doesn’t react easily with the antibiotic," said Strynadka. "Thus, PBP2a can produce sufficient cross-linking in the cell wall so that the bacterium survives."

The researchers’ studies showed that PBP2a is different from normal PBP’s throughout its structure, and not just at the active site. This suggests that the distorted active site is an integral part of the enzyme, said Strynadka. The good news is that the PBP2a active site structure has unique features which can be used to design new types of antibiotics that block its resistance activity.

"The active site of PBP2a is quite extended and relatively hydrophobic," said Strynadka. "The structures we observe now allow for the rational design of specific PBP2a inhibitors that are tailored to better fit these features of the PBP2a active site allowing better affinity and inactivation of the enzyme."

Jim Keeley | Howard Hughes Medical Institute

More articles from Life Sciences:

nachricht Bacteria as pacemaker for the intestine
22.11.2017 | Christian-Albrechts-Universität zu Kiel

nachricht Researchers identify how bacterium survives in oxygen-poor environments
22.11.2017 | Columbia University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Nanoparticles help with malaria diagnosis – new rapid test in development

The WHO reports an estimated 429,000 malaria deaths each year. The disease mostly affects tropical and subtropical regions and in particular the African continent. The Fraunhofer Institute for Silicate Research ISC teamed up with the Fraunhofer Institute for Molecular Biology and Applied Ecology IME and the Institute of Tropical Medicine at the University of Tübingen for a new test method to detect malaria parasites in blood. The idea of the research project “NanoFRET” is to develop a highly sensitive and reliable rapid diagnostic test so that patient treatment can begin as early as possible.

Malaria is caused by parasites transmitted by mosquito bite. The most dangerous form of malaria is malaria tropica. Left untreated, it is fatal in most cases....

Im Focus: A “cosmic snake” reveals the structure of remote galaxies

The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.

Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...

Im Focus: Visual intelligence is not the same as IQ

Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.

That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...

Im Focus: Novel Nano-CT device creates high-resolution 3D-X-rays of tiny velvet worm legs

Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.

During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....

Im Focus: Researchers Develop Data Bus for Quantum Computer

The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.

Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Ecology Across Borders: International conference brings together 1,500 ecologists

15.11.2017 | Event News

Road into laboratory: Users discuss biaxial fatigue-testing for car and truck wheel

15.11.2017 | Event News

#Berlin5GWeek: The right network for Industry 4.0

30.10.2017 | Event News

 
Latest News

Corporate coworking as a driver of innovation

22.11.2017 | Business and Finance

PPPL scientists deliver new high-resolution diagnostic to national laser facility

22.11.2017 | Physics and Astronomy

Quantum optics allows us to abandon expensive lasers in spectroscopy

22.11.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>