Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Using bacterial 'fight clubs' to find new drugs

30.06.2015

Creating bacterial "fight clubs" is an effective way to find new drugs from natural sources.

That is the conclusion of a team of Vanderbilt chemists who have been exploring ways to get bacteria to produce biologically active chemicals that they normally hold in reserve. These compounds are called secondary metabolites.


The 'ring' where the bacteria compete is a flask filled with liquid culture media into which two strains of bacteria are added. The flask is then placed on a shake table to ensure the bacteria are continually coming into contact.

Credit: Anne Rayner, Vanderbilt University

They are designed to protect their bacterial host and attack its enemies, so they often have the right kind of activity to serve as the basis for effective new drugs. In fact, many antibiotics and anticancer compounds in clinical use are either secondary metabolites or their derivatives.

In a proof-of-concept test of the fight-club procedure, the research team headed by Associate Professor of Chemistry Brian Bachmann and Stevenson Professor of Chemistry John McLean discovered a promising new class of natural compounds that exhibit anti-cancer activity. The discovery is reported in the article "Mapping microbial response metabolomes for induced natural product discovery" published online by the journal ACS Chemical Biology on June 17.

Bacteria represent a vast untapped reservoir of biologically active compounds. There are an estimated five million trillion trillion bacterial cells on earth. They come in an astounding variety with the best estimate of the number of distinct species ranging from 120,000 to 150,000.

Analysis of microbial genomes has shown that individual bacteria carry the blueprints for hundreds of secondary metabolites. However, biologists have had a hard time either getting bacteria to produce them or synthesizing them directly so they can assess their therapeutic value.

That's where the "fight club" approach comes in. Research associate Dagmara Derewacz came up with the idea of applying the analytical tools the Bachmann and McLean groups had developed to analyze what happens when microbes compete.

"It's a 'shoot first and ask questions later approach,'" said Bachmann, "which is opposite of the traditional approach to natural products drug discovery."

The first microorganism the scientists put in the ring was Nocardiopsis, a bacteria that is found in the soil. They picked this particular strain because when its genome was sequenced it revealed the presence of 20 gene clusters that carry blueprints for making secondary metabolites.

In order to stimulate the bacteria to produce some of these novel compounds the researchers matched it with four challengers: the common gut organism Escherichia coli; Bacillus subtilis, a well-studied model organism; Tsukamurella pulmonis, which infects people with compromised immune systems; and, Rhodococcus wratislaviensis, which degrades hydrocarbons.

The researchers "co-cultured" Nocoardiopsis separately with each of the challenger microorganisms.

"What Brett Covington in my lab found and quantified was that in every case that the product - the co-culture - was more than the sum of the two monocultures," said Bachmann. "The co-cultures contained significantly more kinds of biological molecules than the two monocultures combined."

The researchers were able to make this determination because of an advanced analytical chemistry technique capable of simultaneously identifying thousands of different biological compounds, which McLean and colleagues have helped pioneer. This technology, called ion mobility-mass spectrometry, combines ion mobility spectroscopy that separates and identifies electrically charged molecules by the speed with which they travel through a gas-filled column with mass spectrometry that precisely "weighs" individual molecules by how quickly they travel a given distance in the absence of gas.

The chemists estimate that the cell co-cultures contain somewhere between 20,000 to 50,000 different kinds of molecules. Ion mobility - mass spectroscopy separates these molecules based on their size-to-weight ratio, which naturally sorts them into different regions that correspond to proteins, lipids, sugars, metabolites etc., and allows them to identify about 2,500 metabolites in each co-culture.

One of the biggest technical challenges stems from the wide range in concentrations of different molecules: the bacteria produce some compounds by the dozens but make others by the billions.

The secondary metabolites that the researchers were looking for are generally present in relatively low concentrations, so they had to come up with a method that helped them identify these compounds based on their qualities not their quantities.

They call the method they developed "self-organizing metabolomics maps" or SOM. "SOM is similar to the process Amazon uses to make recommendations for the products they sell," said McLean.

Amazon monitors your Internet page views, your purchasing history and other information they have about you and make a pattern out of the data. It puts your pattern on a tile and does the same for its millions of other customers. Next, it shuffles these tiles around until neighboring tiles share the most similar patterns. Then they recommend your last purchase to your neighbors and their last purchases to you.

"The SOMs we are using here do much the same thing. They take the patterns in the data we have about all these molecules and match those that behave similarly," said McLean.

This procedure allowed the chemists to discover a new member of a class of biomolecules with broad ranging activity produced when Nocoardiopsis comes into contact with Rhodococcus wratislaviensis. The scientists named this new compound ciromicin, after a Latin word meaning war/cite/disturb/invoke. Circomicn's structure is similar to that of several FDA-approved antibiotics. The new compound has demonstrated both anti-tumor activity in vitro and the capability to modulate genes involved in programmed cell death.

"In the past, we've experimented with a number of ways to get bacteria to produce their secondary metabolites, including poisoning them with antibiotics and exposing them to rare earths, but the fight club approach is the most effective method we've found, by far," said McLean.

###

The research was supported by National Institutes of Health grants GM092218 and T32 GM 0650086. Visit Research News @ Vanderbilt for more research news from Vanderbilt.

David Salisbury | Vanderbilt University

Further reports about: SOM Vanderbilt antibiotics bacteria drugs metabolites organism

More articles from Health and Medicine:

nachricht Similarities found in cancer initiation in kidney, liver, stomach, pancreas
21.02.2018 | Washington University School of Medicine

nachricht 'Living bandages': NUST MISIS scientists develop biocompatible anti-burn nanofibers
16.02.2018 | National University of Science and Technology MISIS

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

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

Im Focus: In best circles: First integrated circuit from self-assembled polymer

For the first time, a team of researchers at the Max-Planck Institute (MPI) for Polymer Research in Mainz, Germany, has succeeded in making an integrated circuit (IC) from just a monolayer of a semiconducting polymer via a bottom-up, self-assembly approach.

In the self-assembly process, the semiconducting polymer arranges itself into an ordered monolayer in a transistor. The transistors are binary switches used...

Im Focus: Demonstration of a single molecule piezoelectric effect

Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale

Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...

Im Focus: Hybrid optics bring color imaging using ultrathin metalenses into focus

For photographers and scientists, lenses are lifesavers. They reflect and refract light, making possible the imaging systems that drive discovery through the microscope and preserve history through cameras.

But today's glass-based lenses are bulky and resist miniaturization. Next-generation technologies, such as ultrathin cameras or tiny microscopes, require...

Im Focus: Stem cell divisions in the adult brain seen for the first time

Scientists from the University of Zurich have succeeded for the first time in tracking individual stem cells and their neuronal progeny over months within the intact adult brain. This study sheds light on how new neurons are produced throughout life.

The generation of new nerve cells was once thought to taper off at the end of embryonic development. However, recent research has shown that the adult brain...

Im Focus: Interference as a new method for cooling quantum devices

Theoretical physicists propose to use negative interference to control heat flow in quantum devices. Study published in Physical Review Letters

Quantum computer parts are sensitive and need to be cooled to very low temperatures. Their tiny size makes them particularly susceptible to a temperature...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

2nd International Conference on High Temperature Shape Memory Alloys (HTSMAs)

15.02.2018 | Event News

Aachen DC Grid Summit 2018

13.02.2018 | Event News

How Global Climate Policy Can Learn from the Energy Transition

12.02.2018 | Event News

 
Latest News

MEMS chips get metatlenses

21.02.2018 | Physics and Astronomy

International team publishes roadmap to enhance radioresistance for space colonization

21.02.2018 | Physics and Astronomy

World's first solar fuels reactor for night passes test

21.02.2018 | Earth Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>