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 New imaging study reveals how saturated fatty acids damage cells
04.12.2017 | Columbia University

nachricht New Diagnostic Tool Aids Quality Control in Xenotransplantations
04.12.2017 | Helmholtz-Zentrum für Infektionsforschung

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Virtual Reality for Bacteria

An interdisciplinary group of researchers interfaced individual bacteria with a computer to build a hybrid bio-digital circuit - Study published in Nature Communications

Scientists at the Institute of Science and Technology Austria (IST Austria) have managed to control the behavior of individual bacteria by connecting them to a...

Im Focus: A space-time sensor for light-matter interactions

Physicists in the Laboratory for Attosecond Physics (run jointly by LMU Munich and the Max Planck Institute for Quantum Optics) have developed an attosecond electron microscope that allows them to visualize the dispersion of light in time and space, and observe the motions of electrons in atoms.

The most basic of all physical interactions in nature is that between light and matter. This interaction takes place in attosecond times (i.e. billionths of a...

Im Focus: A transistor of graphene nanoribbons

Transistors based on carbon nanostructures: what sounds like a futuristic dream could be reality in just a few years' time. An international research team working with Empa has now succeeded in producing nanotransistors from graphene ribbons that are only a few atoms wide, as reported in the current issue of the trade journal "Nature Communications."

Graphene ribbons that are only a few atoms wide, so-called graphene nanoribbons, have special electrical properties that make them promising candidates for the...

Im Focus: Quantum internet goes hybrid

In a recent study, published in Nature, ICFO researchers Nicolas Maring, Pau Farrera, Dr. Kutlu Kutluer, Dr. Margherita Mazzera, and Dr. Georg Heinze led by ICREA Prof. Hugues de Riedmatten, have achieved an elementary "hybrid" quantum network link and demonstrated for the first time photonic quantum communication between two very distinct quantum nodes placed in different laboratories, using a single photon as information carrier.

Today, quantum information networks are ramping up to become a disruptive technology that will provide radically new capabilities for information processing...

Im Focus: New proton record: Researchers measure magnetic moment with greatest possible precision

High-precision measurement of the g-factor eleven times more precise than before / Results indicate a strong similarity between protons and antiprotons

The magnetic moment of an individual proton is inconceivably small, but can still be quantified. The basis for undertaking this measurement was laid over ten...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Blockchain is becoming more important in the energy market

05.12.2017 | Event News

Ecology Across Borders: International conference brings together 1,500 ecologists

15.11.2017 | Event News

Road into laboratory: Users discuss biaxial fatigue-testing for car and truck wheel

15.11.2017 | Event News

 
Latest News

Computer simulations reveal roots of drug resistance

05.12.2017 | Life Sciences

Researchers generate electricity from low-cost biomaterial

05.12.2017 | Materials Sciences

PET identifies which prostate cancer patients can benefit from salvage radiation treatment

05.12.2017 | Medical Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>