The hunt for new antibiotic drugs, driven by emerging diseases and growing bacterial resistance to existing antibiotics, may get a little easier thanks to a new process for making compounds that contain a key bacteria-stopping structure.
The process, developed by a group of researchers led by Thomas Lectka, associate professor of chemistry at The Johns Hopkins University, will make it less expensive to create and easier to test compounds belonging to a class of drugs known as beta-lactams. Penicillin and a number of other infection-fighters are beta-lactams, but bacterial resistance has reduced the usefulness of an increasing number of these drugs.
Lectka, who describes the new process in a report in the online version of The Journal of the American Chemical Society, hopes his work will facilitate the creation of new beta- lactam drugs.
"Beta-lactams have been critical tools for fighting the spread of bacterial infections in the past, and they could be so again," Lectka says. "It's also important to note that while beta-lactams have traditionally been used as antibiotics, they have recently found use in treating patients with conditions ranging from arthritis to HIV."
Beta-lactams's distinguishing characteristic is a high-energy ring of three carbon atoms and one nitrogen atom known as a beta-lactam ring.
"This ring wants to pop open," Lectka explains, "but it doesn't typically do that until a bacterial enzyme comes along and mistakes it for a substrate, a material chemically modified by the enzyme. When the enzyme uses the beta-lactam, the ring snaps open, disabling the enzyme and effectively killing the bacteria."
After decades of overuse of penicillin and other popular antibiotics, though, many bacteria have developed enzymes that disable the beta-lactam rings first. Those enzymes are usually highly specific to one beta-lactam, leaving open the possibility that new beta- lactams might be able to defeat the bacteria. However, researchers interested in making new beta-lactams found themselves confronted with two primary obstacles: cost, and a tricky property called chirality.
Chiral compounds are compounds that can appear in a left-handed or a right- handed form, Lectka explains, noting that each form is known as an enantiomer. Like a pair of human hands, chiral compounds are identical in structure, but their mirror image is not superimposable on the original. Just as trying to put a left-handed glove on your right hand doesn't work, one enantiomer may react with an enzyme while the opposite- handed enantiomer of the same compound does not.
Changing from one enantiomer to another can dramatically alter a drug's biochemical properties, possibly changing an inert substance to a helpful drug or a harmful toxin. One of the most notable cases of this is the drug thalidomide. One enantiomer has beneficial properties, while the other causes birth defects.
"Many of the body's most active chemicals are chiral," Lectka notes, "and they tend to work together like a lock and a key, unleashing positive and sometimes negative effects."
Lectka, who received the prestigious Alfred P. Sloan fellowship earlier this year, is an expert in the field of chemistry known as asymmetric synthesis. Normally, chemical synthesis will produce both left- and right-handed enantiomers, but Lectka and others like him have been developing techniques to synthesize batches of chiral compounds that consist solely of one enantiomer. Such synthesis techniques can aid efforts to design and use new compounds by making it easier for scientists to put the compounds to use without the confounding effects that two enantiomers might present.
A key component to the new beta-lactam synthesis process is the catalyst, a substance that triggers or encourages a chemical reaction without itself being modified by the reaction.
After an extensive search for a catalyst, the Lectka group settled on quinine, which had previously achieved fame as the world's foremost malaria treatment. Quinine occurs naturally in a tree bark, and like many naturally occurring compounds, is enantiomerically pure -- it is made up of only one enantiomer. Enantiomerically pure compounds are generally expensive, Lectka notes, but with a small amount of quinine, a large batch of beta-lactams can be produced. Also, since the quinine is not changed by the reaction, it can be used indefinitely.
Lectka's group is currently adapting their new process so that the catalyst can be used to make other classes of biologically active molecules. He hopes to one day incorporate elements of combinatorial chemistry, which produces a huge variety of compounds at once, and then selectively screens the compounds for desirable properties.
Additional authors of the report were Andrew Taggi, Ahmed Hafez, Harald Wack, Brandon Young, and William Drury III. Lectka's research was funded DuPont; Eli Lilly and Co.; the National Science Foundation, which gave Lectka one of its teacher- scholar awards; and Lectka's Sloan Foundation Fellowship.
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