New look at cell membranes could improve drug testing and design

Research at Arkansas University on membrane proteins could help improve drug development and testing. The chemistry researchers have studied a type of membrane protein that expels drugs from a cell, thus contributing to drug resistance. They found that the lipid composition of the cell membrane had an effect on the behavior of these proteins, which should be taken into account when testing drugs that target membrane proteins. Their results are available for free access in the journal ACS Central Science.

Drug resistance, including bacterial resistance to antibiotics and the resistance of cancer cells to chemotherapy, is a major challenge for drug developers.

"Nearly two-thirds of all drugs target membrane proteins," said Mahmoud Moradi, an badistant professor of chemistry and biochemistry. "This research examines how membrane proteins interact with the environment, and if you do not know that these proteins are dependent on their environment, you may end up with the wrong drugs."

Moradi and his colleagues studied a type of membrane protein called multi-drug ABC exporters. These proteins carry substances, such as drugs, from the inside to the outside of cells, and are responsible for both the antibiotic resistance of bacteria and the resistance to chemotherapy of mammalian cells. .

Using specially designed supercomputers, supported by the National Science Foundation and the National Institutes of Health, researchers performed molecular simulations to study the impact of the lipid composition of the cell membrane on these proteins.

They discovered that these proteins remained inactive and did not expel drugs in cell membranes containing a type of lipid composition, called phosphocholine or PC. However, the same proteins became active in cells with a different lipid composition, called phosphoethanolamine, or PE, allowing them to release drugs and making the cell resistant. Among the cell membranes composed of PE lipids, those containing a particular type of lipid, called POPE, have proved to be the most effective for activating these proteins and therefore most susceptible to drug resistance. Taking into account this information on the lipid environment could help researchers develop and test more effectively antibiotics and cancer treatments.

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More information:
Kalyan Immadisetty et al. Lipid-dependent alternative access mechanism of a multi-drug ABC ABC exporter, ACS Central Science (2019). DOI: 10.1021 / acscentsci.8b00480