1.5: Pump It Up
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Using Ochem Glossary
Organic Chemistry, Transition Metal, Carbocation
Bacteria have an uncanny ability to defend themselves against antibiotics. In trying to figure out why this is so, scientists have noted that antibiotic medicines that kill bacteria in a variety of different ways can be thwarted by the bacteria they are designed to destroy. One reason, says Kim Lewis of Northeastern University in Boston, Massachusetts, may be the bacteria themselves. Microorganisms have ejection systems called multidrug-resistance (MDR) pumps—large proteins that weave through cell-surface membranes. Researchers believe that microbes have MDR pumps mainly for self-defense. The pumps are used to monitor incoming chemicals and to spit out the ones that might endanger the bacteria.
Lewis suggests that plants, which produce many natural bacteria-killing molecules, have gotten "smart" over time, developing ways to outwit bacteria. He suspects that evolution has driven plants to produce natural chemicals that block bacterial MDR pumps, bypassing this bacterial protection system. Lewis tested his idea by first genetically knocking out the gene for the MDR pump from the common bacterium Staphylococcus aureus (S. aureus). He and his coworkers then exposed the altered bacteria to a very weak antibiotic called berberine that had been chemically extracted from barberry plants. Berberine is usually woefully ineffective against S. aureus, but it proved lethal for bacteria missing the MDR pump. What's more, Lewis found that berberine also killed unaltered bacteria given another barberry chemical that inhibited the MDR pumps. Lewis suggests that by co-administering inhibitors of MDR pumps along with antibiotics, physicians may be able to outsmart disease-causing microorganisms.
MDR pumps aren't just for microbes. Virtually all living things have MDR pumps, including people. In the human body, MDR pumps serve all sorts of purposes, and they can sometimes frustrate efforts to get drugs where they need to go. Chemotherapy medicines, for example, are often "kicked out" of cancer cells by MDR pumps residing in the cells' membranes. MDR pumps in membranes all over the body—in the brain, digestive tract, liver, and kidneys—perform important jobs in moving natural body molecules like hormones into and out of cells.
Pharmacologist Mary Vore of the University of Kentucky in Lexington has discovered that certain types of MDR pumps do not work properly during pregnancy, and she suspects that estrogen and other pregnancy hormones may be partially responsible. Vore has recently focused efforts on determining if the MDR pump is malformed in pregnant women who have intrahepatic cholestasis of pregnancy (ICP). A relatively rare condition, ICP often strikes during the third trimester and can cause significant discomfort such as severe itching and nausea, while also endangering the growing fetus. Vore's research on MDR pump function may also lead to improvements in drug therapy for pregnant women.
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