New drugs with that enzymatic touch.

New drugs with that enzymatic touch

Serendipity was key in the discoverynearly 60 years ago that a common mold produced a substance fatal to bacteria -- leading to the broad availability of penicillin. But the present-day search for new drugs, combining computers with chemical acumen, is a far more premediated pursuit. Two studies reported this week, which target specific enzymes essential to disease-causing microorganisms, show just how calculating drug design has become.

At Astra Alab in Sodertalje, in Sweden,scientists have made finely tuned inhibitors of an enzyme needed in the synthesis of lipopolysaccharide (LPS). LPS is found exclusively in the cell walls of gram-negative bacteria, a broad classification that includes Salmonella species, Escherichia coli and many others. Because the inhibitor's target enzyme is not present in mammalian cells, the new class of synthetic drugs will attack certain bacteria and be nontoxic to the host, say the scientists in the June 25 NATURE.

But the group found that making theinhibitors is not enough, since the "foreign" structures cannot pass through the cytoplasmic membranes of bacteria in large engogh amounts to be lethal. The scientists thus used a surprise-attack approach: They linked the inhibitors to protein fragments recognized by several bacterial transport mechanisms, enabling them to be taken into the unsuspecting cells. Once inside, the fragments are degraded and the inhibitors are released, killing the bacteria.

Another study, also reported inNATURE, attempts to optimize the effectiveness of azidothymidine (AZT), the only drug thus far approved in the United States for the treatment of AIDS (SN: 3/28/87, p.198). Scientists at the Wellcome Research Laboratories in Kent, England, cloned the gene for reverse transcriptase, the enzyme necessary for replication of the AIDS virus and the target for AZT. Mutations induced in the gene at selected sites can eliminate activity of the enzyme, say the scientists, who are now inserting the mutant genes back into viruses to see whether such mutations will affect virus growth.