Synthetic route could revitalise tetracycline research

The tetracycline class has been a mainstay of antibiotic therapy since its introduction in the late 1940s, but the emergence of resistance has limited its effectiveness, although tetracyclines are still widely used in human and veterinary medicine. Typically, drug companies overcome resistance by regularly modifying the structure of their antibiotics, trying to stay one step ahead of the bacteria they are trying to combat.

However, difficulties in modifying the structure of tetracyclines, which are semi-synthetic substances based on extraction of a natural precursor from Streptomyces​ species, have held back the development of new drugs in the class. A few product variations were introduced in the mid 20th century, but since the 1960s just three drugs in the class have been introduced, while other antibiotic classes have seen dozens of variations.

Now, the Harvard researchers report a new, wholly synthetic strategy for assembling novel tetracyclines, based on a new way to synthesise the basic ring-structure of the tetracycline precursor molecule. The resulting precursor can be modified easily to generate novel structures that cold form the basis of new antibiotics.

"Complex antibiotics based on natural products are almost invariably prepared by semisynthesis, or chemical transformation of the isolated natural products,"​ say the authors, headed by Mark Charest. "This approach greatly limits the range of accessible structures that might be studied as new antibiotic candidates.​

Using this approach, the researchers were able to synthesise five derivatives were synthesized from benzoic acid in yields ranging from 5 to 7 per cent over 14- to 15-step reactions, and a sixth was synthesized with a yield of 8.3 per cent over 18 steps. This is not yet suitable for commercial-scale production, but can produce amounts suitable for drug discovery and early-stage development.

In an editorial accompanying the study, Chaitan Khosla of Stanford University and Yi Tang of the University of California Los Angeles - who have themselves developed new biosynthetic strategies for making polyketides (the overarching chemical group which counts tetracycline as a member) - said the technique 'enormously expands the armamentarium of the tetracycline medicinal chemist'.

Tetracycline research has not been completely barren however. One tetracycline-related product from Wyeth, called tigecycline, has reached late-stage development and is tipped to become a major player the fight against multidrug-resistant micro-organisms, including methicillin-resistant Staphylococcus aureus​ (MRSA), vancomycin-resistant enterococci and resistant Gram-negative infections.