Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Scripps Research Institute Chemists Modify Antibiotic to Vanquish Resistant Bacteria

18.09.2014

Scientists at The Scripps Research Institute (TSRI) have devised a new antibiotic based on vancomycin that is powerfully effective against vancomycin-resistant strains of MRSA and other disease-causing bacteria.

The new vancomycin analog appears to have not one but two distinct mechanisms of anti-microbial action, against which bacteria probably cannot evolve resistance quickly.

“This is the prototype of analogues that once introduced will still be in clinical use a generation or maybe even two generations from now,” said Dale L. Boger, the Richard and Alice Cramer Professor of Chemistry at TSRI.

The report by Boger and members of his laboratory was published recently online ahead of print by the Journal of the American Chemical Society.

Increasing Reports of Resistance

Vancomycin entered clinical use in 1958, five years after its isolation from microbes in a soil sample gathered by an American missionary in Borneo. For nearly six decades it has been useful against a wide range of bacteria, and it remains a standard weapon against methicillin-resistant Staphylococcus aureus (MRSA), a major cause of hospital-acquired infections. A compound closely related to vancomycin also has been widely used to protect livestock.

Since the late 1980s, there have been increasing reports of vancomycin resistance in classes of bacteria that usually succumb to the antibiotic, including MRSA. Although vancomycin remains useful, scientists have been looking for new drugs to replace it in cases—often life-threatening—where it no longer can help patients.

The Boger laboratory has focused on inventing improved versions of vancomycin rather than entirely new compounds. “Vancomycin has lasted in clinical use for more than 50 years, in part because it isn’t very vulnerable to antibiotic resistance,” Boger said. “Our thought has been that if we find a vancomycin analog that addresses this current source of resistance we’ll get another 50 years of use out of it.”

Vancomycin works by binding to the building blocks of bacterial cell walls, in a way that prevents their proper assembly and leaves bacteria too leaky to live and replicate. The resistance comes from a single amino-acid alteration that some bacteria make to those building blocks, so that the antibiotic molecule can no longer get a firm grip. That drops vancomycin’s potency by a factor of about 1,000.

‘Incredibly Potent’

In 2012, Boger and his team reported making a vancomycin analog—informally termed vancomycin amidine—with a subtly altered binding pocket that fastens about equally well to the original and resistant sites on bacterial cell wall subunits. To get the precise structural modification they needed, they had to come up with a method for the “total synthesis” of this vancomycin-based compound—a controlled, step-by-step construction using organic chemistry reactions in the lab, rather than a natural enzyme-mediated production within cells.

“Years of work in this lab culminated in a total synthesis strategy that not only allowed us access to this target compound, but also gave us the ability to perform almost any other chemical modification of vancomycin that we wished,” said Akinori Okano, first author of the new report, who is an assistant professor of chemistry at TSRI.

Vancomycin amidine turned out to have acceptable level of activity against vancomycin-resistant and -sensitive bacteria, yet there was room for improvement. Thus in the new study, Okano, Boger and their colleagues used their vancomycin synthesis methods to add an additional feature to the molecule—a peripheral chlorobiphenyl (CBP), long known as a general booster of vancomycin’s potency.

“To our delight, the combination of these modifications led to an incredibly potent molecule, well beyond anything we had expected,” said Okano.

In lab dish tests, the new vancomycin analog proved highly effective against the usual vancomycin-sensitive bacteria as well as vancomycin-resistant MRSA and enterococcal bacteria.

The tests also suggested that the CBP modification, whose boost to potency has been thought to come from some broad enhancement of vancomycin’s activity, might in fact work via its own distinct attack on bacterial cell wall synthesis.

“This is probably the clearest depiction to date of the fact that for the CBP derivatives there must be a second mechanism of action, independent of vancomycin’s main mechanism of action,” Boger said. “[Such analogs] are likely to display especially durable antibiotic activity—that is, they won’t be prone to rapidly acquired clinical resistance.”

Boger and his colleagues now will try to optimize the synthesis process for the new analog, to provide quantities suitable for preclinical testing in animals.

Other co-authors of the paper, “Total Synthesis of [Ψ[C(=NH)NH]Tpg4] Vancomycin and its (4-Chlorobiphenyl) methyl Derivative: Impact of Peripheral Modifications on Vancomycin Analogs Redesigned for Dual D-Ala-D-Ala and D-Ala-D-Lac Binding,” were Atsushi Nakayama and Alex Schammel of the Boger Laboratory. For more information, see http://pubs.acs.org/doi/abs/10.1021/ja507009a?journalCode=jacsat

The research was supported by the National Institutes of Health (grant CA041101).

About The Scripps Research Institute

The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs about 3,000 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including three Nobel laureates—work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.

For information:
Office of Communications
Tel: 858-784-2666
Fax: 858-784-8136
press@scripps.edu

Madeline McCurry Schmidt | Eurek Alert!
Further information:
http://www.scripps.edu/news/press/2014/20140917boger.html

Further reports about: CBP MRSA TSRI antibiotic bacteria bacterial cell mechanism resistance synthesis vancomycin

More articles from Life Sciences:

nachricht Molecular Force Sensors
20.09.2017 | Max-Planck-Institut für Biochemie

nachricht Foster tadpoles trigger parental instinct in poison frogs
20.09.2017 | Veterinärmedizinische Universität Wien

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Tiny lasers from a gallery of whispers

New technique promises tunable laser devices

Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...

Im Focus: Ultrafast snapshots of relaxing electrons in solids

Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!

When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...

Im Focus: Quantum Sensors Decipher Magnetic Ordering in a New Semiconducting Material

For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.

Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...

Im Focus: Fast, convenient & standardized: New lab innovation for automated tissue engineering & drug

MBM ScienceBridge GmbH successfully negotiated a license agreement between University Medical Center Göttingen (UMG) and the biotech company Tissue Systems Holding GmbH about commercial use of a multi-well tissue plate for automated and reliable tissue engineering & drug testing.

MBM ScienceBridge GmbH successfully negotiated a license agreement between University Medical Center Göttingen (UMG) and the biotech company Tissue Systems...

Im Focus: Silencing bacteria

HZI researchers pave the way for new agents that render hospital pathogens mute

Pathogenic bacteria are becoming resistant to common antibiotics to an ever increasing degree. One of the most difficult germs is Pseudomonas aeruginosa, a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

“Lasers in Composites Symposium” in Aachen – from Science to Application

19.09.2017 | Event News

I-ESA 2018 – Call for Papers

12.09.2017 | Event News

EMBO at Basel Life, a new conference on current and emerging life science research

06.09.2017 | Event News

 
Latest News

Molecular Force Sensors

20.09.2017 | Life Sciences

Producing electricity during flight

20.09.2017 | Power and Electrical Engineering

Tiny lasers from a gallery of whispers

20.09.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>