Chemists Develop High-Throughput Method To Synthesize And Screen Novel Antibiotics

September 08, 1997

Cincinnati -- University of Cincinnati researchers have developed a system for quickly synthesizing and screening potential replacements for standard antibiotics, such as penicillin and amoxicillin. All of these antibiotics fall into the category known as beta lactams.

Chemistry graduate student Jie Wang will explain a key part of the system Sunday, Sept. 7 during the national meeting of the American Chemical Society in Las Vegas.

The system, developed by Professor Richard Day, uses a patented intermediate compound (a Leuchs anhydride) for rapid synthesis of novel antibiotics. It is coupled with a high- throughput method for screening the compounds' activity. The complete process takes about two days.

"We have over 1,000 novel beta lactams," said Day. "Most of them test out as being very effective against a wide range of bacteria."

More importantly, several of the compounds are effective at extremely low levels. The typical minimum inhibitory concentration (or MIC) of prescription beta lactams falls between 0.1 and 1.0 microgram per milliliter. Some of the compounds developed in Day's lab were effective at the sub-nanogram level.

That might make it possible to develop antibiotic skin patches. The patches have an advantage over pills, because the patient would not have to remember when to take medicine, and doctors would not have to worry that the patient did not finish all the medication.

The most promising antibiotics have been tested in the lab against both Gram-negative and Gram-positive bacteria, against resistant and non-resistant strains of bacteria, and against a "defanged" version of the microbe that causes tuberculosis.

The results were encouraging, although Day knows these compounds have a long way to go before any of them could reach human testing. "We can make beta lactams that take out the tuberculosis bacteria without any trouble, but there's a big jump between the test tube and elsewhere," Day readily admits.

The focus of Wang's presentation will be on the analytical methods used to identify and separate the various isomers produced by Day's synthetic approach.

"The important result to having access to all these isomers is we found some are lytic and some are non-lytic to bacteria," said Day.

The lytic antibiotics actually burst open the bacterial cells. The non-lytic forms inhibit growth without destroying the bacteria. That's important, because some bacteria contain extremely dangerous toxins which can cause severe complications. For example, the plague bacteria contains a heart toxin and the bacteria which causes meningitis contains a neurotoxin. Non-lytic antibiotics may prove to be much safer than currently available drugs.
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University of Cincinnati

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