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 Good preparation is half the digestion
15.11.2018 | Max-Planck-Institut für Stoffwechselforschung

nachricht How the gut ‘talks’ to brown fat
16.11.2018 | Technische Universität München

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 Chip with Blood Vessels

Biochips have been developed at TU Wien (Vienna), on which tissue can be produced and examined. This allows supplying the tissue with different substances in a very controlled way.

Cultivating human cells in the Petri dish is not a big challenge today. Producing artificial tissue, however, permeated by fine blood vessels, is a much more...

Im Focus: A Leap Into Quantum Technology

Faster and secure data communication: This is the goal of a new joint project involving physicists from the University of Würzburg. The German Federal Ministry of Education and Research funds the project with 14.8 million euro.

In our digital world data security and secure communication are becoming more and more important. Quantum communication is a promising approach to achieve...

Im Focus: Research icebreaker Polarstern begins the Antarctic season

What does it look like below the ice shelf of the calved massive iceberg A68?

On Saturday, 10 November 2018, the research icebreaker Polarstern will leave its homeport of Bremerhaven, bound for Cape Town, South Africa.

Im Focus: Penn engineers develop ultrathin, ultralight 'nanocardboard'

When choosing materials to make something, trade-offs need to be made between a host of properties, such as thickness, stiffness and weight. Depending on the application in question, finding just the right balance is the difference between success and failure

Now, a team of Penn Engineers has demonstrated a new material they call "nanocardboard," an ultrathin equivalent of corrugated paper cardboard. A square...

Im Focus: Coping with errors in the quantum age

Physicists at ETH Zurich demonstrate how errors that occur during the manipulation of quantum system can be monitored and corrected on the fly

The field of quantum computation has seen tremendous progress in recent years. Bit by bit, quantum devices start to challenge conventional computers, at least...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

“3rd Conference on Laser Polishing – LaP 2018” Attracts International Experts and Users

09.11.2018 | Event News

On the brain’s ability to find the right direction

06.11.2018 | Event News

European Space Talks: Weltraumschrott – eine Gefahr für die Gesellschaft?

23.10.2018 | Event News

 
Latest News

Massive impact crater from a kilometer-wide iron meteorite discovered in Greenland

15.11.2018 | Earth Sciences

When electric fields make spins swirl

15.11.2018 | Physics and Astronomy

Discovery of a cool super-Earth

15.11.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>