Biochemistry

Flipped Out

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Science  12 May 2006:
Vol. 312, Issue 5775, pp. 815
DOI: 10.1126/science.312.5775.815b

As a consequence of their competitive upbringing, microbes have refined the art of warfare, both in the synthesis of and resistance to small molecules, many of which are used by humans as antibiotic drugs. The modes whereby the microbes resist the action of drugs fall generally into three classes: (i) chemical modification of the small molecule into a harmless derivative (for instance, by hydrolysis); (ii) protection of the protein targeted by the drug (by mutation of the gene); (iii) sequestration or transport of the drug beyond the vicinity of the target (by pumping the drug out of the cell).

Siarheyeva et al. have taken a closer look at the last of these pathways and address a current controversy regarding the environment and mechanism used to load substrates into the multidrug-resistance transporters for removal. By applying nuclear magnetic resonance spectroscopy to detect the interactions between (the protons of) nine representative and structurally dissimilar drugs and (the protons of) dimyristoyl phosphatidylcholine, the authors find that all of these hydrophobic compounds reside predominantly in the portion of the lipid bilayer between the choline headgroup and the aliphatic tails. This location is consistent with the view that multidrug-resistance transporters may function primarily to flip drugs from the inner to the outer leaflet of the plasma membrane, from whence the drugs diffuse into the extracellular medium, thus reducing intracellular antibiotic concentrations. — GJC

Biochemistry 45, 10.1021/bi0524870 (2006).

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