Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Computer simulations reveal roots of drug resistance


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,

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 Molecular doorstop could be key to new tuberculosis drugs
20.03.2018 | Rockefeller University

nachricht Modified biomaterials self-assemble on temperature cues
20.03.2018 | Duke University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Mars' oceans formed early, possibly aided by massive volcanic eruptions

Oceans formed before Tharsis and evolved together, shaping climate history of Mars

A new scenario seeking to explain how Mars' putative oceans came and went over the last 4 billion years implies that the oceans formed several hundred million...

Im Focus: Tiny implants for cells are functional in vivo

For the first time, an interdisciplinary team from the University of Basel has succeeded in integrating artificial organelles into the cells of live zebrafish embryos. This innovative approach using artificial organelles as cellular implants offers new potential in treating a range of diseases, as the authors report in an article published in Nature Communications.

In the cells of higher organisms, organelles such as the nucleus or mitochondria perform a range of complex functions necessary for life. In the networks of...

Im Focus: Locomotion control with photopigments

Researchers from Göttingen University discover additional function of opsins

Animal photoreceptors capture light with photopigments. Researchers from the University of Göttingen have now discovered that these photopigments fulfill an...

Im Focus: Surveying the Arctic: Tracking down carbon particles

Researchers embark on aerial campaign over Northeast Greenland

On 15 March, the AWI research aeroplane Polar 5 will depart for Greenland. Concentrating on the furthest northeast region of the island, an international team...

Im Focus: Unique Insights into the Antarctic Ice Shelf System

Data collected on ocean-ice interactions in the little-researched regions of the far south

The world’s second-largest ice shelf was the destination for a Polarstern expedition that ended in Punta Arenas, Chile on 14th March 2018. Oceanographers from...

All Focus news of the innovation-report >>>



Industry & Economy
Event News

Virtual reality conference comes to Reutlingen

19.03.2018 | Event News

Ultrafast Wireless and Chip Design at the DATE Conference in Dresden

16.03.2018 | Event News

International Tinnitus Conference of the Tinnitus Research Initiative in Regensburg

13.03.2018 | Event News

Latest News

Physicists made crystal lattice from polaritons

20.03.2018 | Physics and Astronomy

Mars' oceans formed early, possibly aided by massive volcanic eruptions

20.03.2018 | Physics and Astronomy

Thawing permafrost produces more methane than expected

20.03.2018 | Earth Sciences

Science & Research
Overview of more VideoLinks >>>