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 A Map of the Cell’s Power Station
18.08.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau

nachricht On the way to developing a new active ingredient against chronic infections
18.08.2017 | Deutsches Zentrum für Infektionsforschung

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.

As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

 
Latest News

A Map of the Cell’s Power Station

18.08.2017 | Life Sciences

Engineering team images tiny quasicrystals as they form

18.08.2017 | Physics and Astronomy

Researchers printed graphene-like materials with inkjet

18.08.2017 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>