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 Scientists uncover the role of a protein in production & survival of myelin-forming cells
19.07.2018 | Advanced Science Research Center, GC/CUNY

nachricht NYSCF researchers develop novel bioengineering technique for personalized bone grafts
18.07.2018 | New York Stem Cell Foundation

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: First evidence on the source of extragalactic particles

For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.

To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...

Im Focus: Magnetic vortices: Two independent magnetic skyrmion phases discovered in a single material

For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.

Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...

Im Focus: Breaking the bond: To take part or not?

Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.

A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...

Im Focus: New 2D Spectroscopy Methods

Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.

"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....

Im Focus: Chemical reactions in the light of ultrashort X-ray pulses from free-electron lasers

Ultra-short, high-intensity X-ray flashes open the door to the foundations of chemical reactions. Free-electron lasers generate these kinds of pulses, but there is a catch: the pulses vary in duration and energy. An international research team has now presented a solution: Using a ring of 16 detectors and a circularly polarized laser beam, they can determine both factors with attosecond accuracy.

Free-electron lasers (FELs) generate extremely short and intense X-ray flashes. Researchers can use these flashes to resolve structures with diameters on the...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Leading experts in Diabetes, Metabolism and Biomedical Engineering discuss Precision Medicine

13.07.2018 | Event News

Conference on Laser Polishing – LaP: Fine Tuning for Surfaces

12.07.2018 | Event News

11th European Wood-based Panel Symposium 2018: Meeting point for the wood-based materials industry

03.07.2018 | Event News

 
Latest News

Global study of world's beaches shows threat to protected areas

19.07.2018 | Earth Sciences

New creepy, crawly search and rescue robot developed at Ben-Gurion U

19.07.2018 | Power and Electrical Engineering

Metal too 'gummy' to cut? Draw on it with a Sharpie or glue stick, science says

19.07.2018 | Materials Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>