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New class of antibiotics confirmed.

New class of antibiotics confirmed

It was quite by chance that Alexander Fleming in 1928 discovered penicillin. Since then, many antibiotics have been developed, but the serendipitous route of discovery has changed very little. Antibiotics are to this day being patiently sought in naturally occurring substances such as tropical plant extracts and soil molds.

In recent years, however, as molecular biologists have become more proficient at making customized biochemical compounds, interest in "rational drug design' has increased. Rather than looking for naturally occurring drugs--or modifying already-discovered ones--scientists are attempting to craft extremely specific molecules that are capable of killing pathogens without harming the human host.

The first successful synthesis of a rationally designed antibiotic was reported by Swedish researchers in late June of this year. Now scientists working independently at Abbott Laboratories in Abbott Park, Ill., report success with a similar "designer' drug. Tests have so far been restricted to laboratory cultures of disease-causing bacteria. But the research confirms the potential of this new class of antibiotics and provides some encouraging details about how effective the drugs are apt to be.

Robert Goldman and his co-workers report in the Sept. 10 NATURE the synthesis of a potent antibiotic that is effective against an important class of dis-ease-causing microbes--the gram-negative bacteria. Gram-negative bacteria cause a large number of diseases, including gonorrhea, cholera, meningitis and a variety of dysenteries.

"Even penicillin-resistant, eryth-romycin-resistant and tetracycline-resistant organisms are still sensitive to this compound because it's an entirely different metabolic pathway that's being affected,' Goldman told SCIENCE NEWS. The compound inhibits an enzyme inside the bacterial cell that is crucial for the production of lipopolysaccharide--an important component of the bacterial cell membrane. The resulting defective membrane leaves the bacteria unable to reproduce, while rendering them up to 10 times more susceptible to standard antibiotics.

The synthesis of such a specific inhibitor is the culmination of years of research in which the critical bacterial enzyme--CMP-KDO synthetase--was identified, isolated and eventually cloned. Using nuclear magnetic resonance, scientists determined its structure in 1985. On the basis of that information, they designed an inhibitor to mimic the enzyme's natural target, or substrate.

"It's a very straightforward competitive inhibitor of the enzyme,' Goldman says. "When the inhibitor [drug] binds to the active site of the enzyme, the enzyme has no access to the real substrate. But the enzyme can't do anything with the inhibitor, so it just sits there, dead.'

Moreover, he says, the targeted enzyme "is unique to gram-negative bacteria, so you don't have to worry about inhibiting some analogous pathway in the human.'

Encouraging as the research is, work remains to be done before the drug will be ready for clinical trials. Most important, Goldman says, improvements need to be made in the peptide delivery system that carries the drug into the bacterial cell. Because the inhibitor does its duty inside the bacterium, but is itself incapable of penetrating the bacterial membrane, it requires a carrier molecule to get it across. Currently, researchers are binding the drug to tiny peptides that are naturally capable of crossing that membrane. Once inside the bacterium, intracellular enzymes cleave the molecular complex, releasing the drug.

"The peptide gets the compound in sort of like the Trojan horse, and then you clip off those amino acids to release that warhead molecule,' Goldman says. However, the carrier peptides now being used do not penetrate all gram-negative bacteria equally well. So although all gram-negative bacteria contain CMP-KDO synthetase --and are theoretically susceptible to the enzyme inhibitor--not all of them are equally vulnerable to the invading antibiotic. Other peptide carriers may prove more invasive for a broader spectrum of bacteria.

A second problem is that peptide carriers tend to be very short-lived in the human body. Improvements are needed, Goldman says, "so that the compounds will stay around long enough to do their job.'
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Title Annotation:rational drug design
Author:Weiss, Rick
Publication:Science News
Date:Sep 19, 1987
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