LONDON — A new generation of penicillin-based antibiotics capable of killing even penicillin-resistant organisms may be in sight, following a discovery by a team of researchers in Ireland.

Chemists working at the University of Limerick said a new molecule they have discovered could put bacteria into "checkmate," killing them even when they are resistant to penicillin.

Timothy Smyth, senior lecturer in organic chemistry at the University of Limerick, told BioWorld International: "We believe that this discovery could be exceptionally significant." Some "very good" candidate compounds for clinical testing could be available within two years, he predicted, depending on what resources are invested in developing the idea. Smyth and his collaborators are seeking partners in the pharmaceutical industry to help them pursue their research.

Resistance to penicillin and other antibiotics is the bane of clinicians worldwide. Over 95 percent of isolates of Staphylococcus aureus, a bacterium which infects wounds, were susceptible to penicillin when it was introduced in 1944, but now only 10 percent succumb to the drug.

As reported by the U.K. Standing Medical Advisory Committee Sub-Group on Antimicrobial Resistance earlier this year, resistance to penicillin by Streptococcus pneumoniae — the cause of community-acquired pneumonia, and a common cause of ear infections in children and of bacterial meningitis — is also on the increase. A survey in the U.K. showed that, while 1.5 percent of S. pneumoniae isolates were resistant to penicillin in 1990, this figure had risen to 3.9 percent by 1995.

Studies from other European countries, quoted in the same report, have reported much more discouraging figures. For example, greater than 50 percent of strains of S. pneumoniae were resistant in Hungary in 1988 and 1989, and greater than 40 percent in Spain in 1989.

The work by Smyth and his colleagues represents a new approach to the development of antibiotics that deal with the problem of bacterial resistance. They report their findings in the Oct. 9 Web edition of the Journal of Organic Chemistry, which is published by the American Chemical Society. The paper is titled: "S-aminosulfeniminopenicillins: multimode ß-lactamase inhibitors and template structures for penicillin-based ß-lactamase substrates as prodrugs."

Next Challenge: Designing The Molecule

Penicillins and related antibiotics selectively destroy bacteria by blocking the action of a vital enzyme found only in bacteria, called transpeptidase. Penicillin-resistant bacteria, however, produce an enzyme which attacks penicillin before it can get as far as inhibiting transpeptidase. This enzyme is called ß-lactamase, because it attacks a part of the penicillin molecule called the ß-lactam ring.

To counter this problem, chemists have developed compounds which inhibit ß-lactamase. But after a few generations, the bacteria mutate so that the ß-lactamase they produce is no longer susceptible to the inhibitors. More than 240 different types of ß-lactamase have now been identified, following the introduction of such drugs.

The Irish team considered putting some unusual side chains on the penicillin molecule. Smyth told BioWorld International: "We put a sulphur-based group onto the molecule, attaching it on to the amine group which is found on the ß-lactam ring. When we added ß-lactamase to this modified penicillin molecule, what followed was a type of reaction that has never been reported before."

In the presence of ß-lactamase, which cleaved to the ß-lactam ring, the modified molecule underwent a rapid intramolecular reaction. The sulphur in the added side-chain came into close proximity with a second sulphur molecule elsewhere in the molecule, with the result that the remainder of the side-chain was eliminated from the molecule.

Smyth explained: "Intact penicillin is bicyclic and very rigid. The sulphur on the side chain and the sulphur in the molecule are actually held apart. But when the ring is cleaved by ß-lactamase, it allows these two sulphurs to get into a position where they react very rapidly. This means that whatever is attached to the sulphur of the side chain is kicked out — and it should be fairly straightforward to design it so that the expelled moiety is fatal to the bacterium, in a typical pro-drug strategy."

The trick now is to design a molecule which will fulfil the team's ideal for a checkmate stratagem. Two modifications are necessary. One is needed to ensure that the modified penicillin molecule behaves just like normal penicillin, so that if it encounters non-resistant bacteria, these are still killed by it. The second is to find the pro-drug which is harmless until released from the eliminated side chain.

The Irish researchers have shown that having a group linked either via an oxygen or a nitrogen atom to the side chain sulphur gave the same reaction. "This is significant because, in terms of being able to vary the part that is displaced, it is a huge boon not to be restricted to one type of linkage," Smyth explained.

What could drugs of this kind mean for the future evolution of disease-causing bacteria?

"By the widespread use of antibiotics," Smyth speculated, "we have put an evolutionary pressure on bacteria, and the ones which have survived well are the ones which could get rid of penicillin. Conversely, you could envisage a scenario where compounds prepared from our prototype would be more effective against those bacteria which have this resistant characteristic. They would therefore have no survival advantage over bacteria which were not resistant. So one should be able to push the equilibrium back towards where it was earlier this century." *

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