Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Computer simulations reveal roots of drug resistance

05.12.2017

Deactivating pumps could make antibiotic-resistant bacteria treatable again

New supercomputer simulations have revealed the role of transport proteins called efflux pumps in creating drug-resistance in bacteria, research that could lead to improving the drugs' effectiveness against life-threatening diseases and restoring the efficacy of defunct antibiotics.


Bacterial efflux pumps, such as the P. aeruginosa MexAB-OprM pump shown here, are one of the dominant molecular mechanisms available to Gram-negative pathogens for removing toxins, including antibiotics. Inactivation of the pump assembly and function would be a major step for reducing bacterial multidrug resistance.

Credit: LANL

"By understanding how the pump moves and dynamically behaves, we can potentially find a way to deactivate the pump--and antibiotics that haven't worked in a long time may be useful again," said Los Alamos biophysicist Gnana Gnanakaran, who collaborated with colleagues at the Laboratory and with bacterial efflux pump experts Helen Zgurskaya at the University of Oklahoma and Klaas Pos at Goethe University in Frankfurt, Germany.

Some life-threatening infections do not respond to antibiotics because efflux pumps inside a particular type of infectious microbe called Gram-negative bacteria flush out antibiotics before the drugs can work. One type of efflux pump, which until recently had only been studied in parts, was recently modeled in its entirety and simulated using supercomputers at Los Alamos National Laboratory.

The findings, published November 28 in Scientific Reports, offer a better understanding of the motions and functions of efflux pumps. The work exploits the Laboratory's extensive modeling and supercomputing simulation capabilities developed in support of its national security mission.

For this study, the researchers focused on efflux pumps inside the bacteria Pseudomonas aeruginosa, which can cause serious illnesses such as pneumonia and sepsis. In P. aeruginosa, the major pump type is called MexAB-OprM and composed of three proteins: MexA, MexB and OprM.

"This is a really, really large system--approximately a million and a half atoms," said Laboratory theoretical biologist Cesar A. López. The MexAB-OprM pump encompasses both inner and outer membranes found in Gram-negative bacteria and connects the cell's interior and periplasm (the compartment between both membranes) to the cell's exterior. That connection creates a path for drug molecules to exit the cell.

The Laboratory's supercomputers were able to perform the first atomistic simulations of the entire MexAB-OprM pump embedded within a double membrane system on a microsecond time scale.

The researchers then used the simulations to investigate the dynamics of the assembled pump and to understand how pump functionality arises from these dynamics. The amino acid interactions that stabilize the complex between MexA and OprM were also independently cross-validated using a computational technique called sequence covariation analysis by Laboratory theoretical biologist Timothy Travers. According to Travers, "This is the first time such a sequence-based technique has been applied for cross-validating the interface of a protein complex built using simulations and cryo-electron microscopy."

Application of these computational techniques to the multitude of efflux pumps found in different Gram-negative pathogens should allow scientists to elucidate if general mechanisms are shared among different pumps or are pump-specific. For example, perhaps the amino acid interactions that stabilize the pump structure could be targeted by drug development efforts to block pump assembly or function, thereby rendering currently defunct antibiotics effective once more.

###

The paper: "Dynamics of Intact MexAB-OprM Efflux Pump: Focusing on the MexA-OprM Interface," Scientific Reports, https://www.nature.com/articles/s41598-017-16497-w

The funding: LDRD-DR

About Los Alamos National Laboratory

Los Alamos National Laboratory, a multidisciplinary research institution engaged in strategic science on behalf of national security, is operated by Los Alamos National Security, LLC, a team composed of Bechtel National, the University of California, BWX Technologies, Inc. and URS Corporation for the Department of Energy's National Nuclear Security Administration. Los Alamos enhances national security by ensuring the safety and reliability of the U.S. nuclear stockpile, developing technologies to reduce threats from weapons of mass destruction, and solving problems related to energy, environment, infrastructure, health and global security concerns.

Nancy Ambrosiano | EurekAlert!

More articles from Life Sciences:

nachricht Colorectal cancer: Increased life expectancy thanks to individualised therapies
20.02.2020 | Christian-Albrechts-Universität zu Kiel

nachricht Sweet beaks: What Galapagos finches and marine bacteria have in common
20.02.2020 | Max-Planck-Institut für Marine Mikrobiologie

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: A step towards controlling spin-dependent petahertz electronics by material defects

The operational speed of semiconductors in various electronic and optoelectronic devices is limited to several gigahertz (a billion oscillations per second). This constrains the upper limit of the operational speed of computing. Now researchers from the Max Planck Institute for the Structure and Dynamics of Matter in Hamburg, Germany, and the Indian Institute of Technology in Bombay have explained how these processes can be sped up through the use of light waves and defected solid materials.

Light waves perform several hundred trillion oscillations per second. Hence, it is natural to envision employing light oscillations to drive the electronic...

Im Focus: Freiburg researcher investigate the origins of surface texture

Most natural and artificial surfaces are rough: metals and even glasses that appear smooth to the naked eye can look like jagged mountain ranges under the microscope. There is currently no uniform theory about the origin of this roughness despite it being observed on all scales, from the atomic to the tectonic. Scientists suspect that the rough surface is formed by irreversible plastic deformation that occurs in many processes of mechanical machining of components such as milling.

Prof. Dr. Lars Pastewka from the Simulation group at the Department of Microsystems Engineering at the University of Freiburg and his team have simulated such...

Im Focus: Skyrmions like it hot: Spin structures are controllable even at high temperatures

Investigation of the temperature dependence of the skyrmion Hall effect reveals further insights into possible new data storage devices

The joint research project of Johannes Gutenberg University Mainz (JGU) and the Massachusetts Institute of Technology (MIT) that had previously demonstrated...

Im Focus: Making the internet more energy efficient through systemic optimization

Researchers at Chalmers University of Technology, Sweden, recently completed a 5-year research project looking at how to make fibre optic communications systems more energy efficient. Among their proposals are smart, error-correcting data chip circuits, which they refined to be 10 times less energy consumptive. The project has yielded several scientific articles, in publications including Nature Communications.

Streaming films and music, scrolling through social media, and using cloud-based storage services are everyday activities now.

Im Focus: New synthesis methods enhance 3D chemical space for drug discovery

After helping develop a new approach for organic synthesis -- carbon-hydrogen functionalization -- scientists at Emory University are now showing how this approach may apply to drug discovery. Nature Catalysis published their most recent work -- a streamlined process for making a three-dimensional scaffold of keen interest to the pharmaceutical industry.

"Our tools open up whole new chemical space for potential drug targets," says Huw Davies, Emory professor of organic chemistry and senior author of the paper.

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

70th Lindau Nobel Laureate Meeting: Around 70 Laureates set to meet with young scientists from approx. 100 countries

12.02.2020 | Event News

11th Advanced Battery Power Conference, March 24-25, 2020 in Münster/Germany

16.01.2020 | Event News

Laser Colloquium Hydrogen LKH2: fast and reliable fuel cell manufacturing

15.01.2020 | Event News

 
Latest News

Active droplets

21.02.2020 | Medical Engineering

Finding new clues to brain cancer treatment

21.02.2020 | Health and Medicine

Beyond the brim, Sombrero Galaxy's halo suggests turbulent past

21.02.2020 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>