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Fighting drug resistance with a Lego-like convergent synthesis strategy of macrolide antibiotics

Antibiotics have had a tremendous impact on human society. The rise of antibiotics in the early 20th century quasi eradicated tuberculosis and syphilis in the developed world and paved the way for a new age in medicine. Likewise, our current and unprecedented level of health and wealth can only be maintained and improved by having control over infectious diseases.

A key problem with the wide-spread use of antibiotics, however, is formation of resistance. By applying evolutionary pressure on a bacterial strain, it is only a question of time until the rapidly evolving unicellular organisms find a mutation that makes them survive the chemical attack. Very recently, it has been reported that multidrug resistant “superbugs” have developed due to overuse of antibiotics on farm animals.[1] In order to keep up with formation of resistance against current drugs it is therefore important to further keep developing new molecular structures.

Molecules that provide antibacterial activity often derive from naturally occurring ones. In particular in the middle of the 20th century, researchers sought novel natural antibiotics, elucidated their structure, and started programs to develop new drugs on this structural basis. One class of drugs that emerged from these efforts is macrolide antibiotics. Those molecules belong to the polyketide class of natural products, featuring a large lactone ring. Famous members are, for instance, eryhthromycin, which is used to treat respiratory infections, chlamydia and syphilis, and clarithromycin, which is used to treat lyme disease among others.

In order to produce and modify the structurally complicated macrolide antibiotics, researchers have mostly turned to semisynthesis by employing natural products derived from fermentation as starting materials for subsequent synthetic modifications. While elegant in many ways, this approach only provides a limited number of possible modifications and thus a small number of potential new drug candidates.

An international team led by Andrew Myers including Daniel Hog and Xiang Zhou has now disclosed “A platform for the discovery of new macrolide antibiotics”.[2] Using simple and modular building blocks, they synthesized over 300 macrolides in a convergent synthesis strategy. This elegant and efficient strategy allowed modifying both the core and installing further substituents in an unprecedented versatility. As a result, structures can be diversified in an “almost exponential manner”. The authors anticipate that “many thousands of novel macrolide structures can be prepared for evaluation as potential antibiotics using the present synthetic platform” and conclude that “developing similar convergent routes to other naturally occurring antibiotic families may accelerate the discovery of new therapeutic agents for human infectious diseases.”    



[1] http://www.nytimes.com/2015/10/20/business/energy-environment/taking-on-the-superbugs-antibiotics.html?_r=0

[2] http://www.nature.com/nature/journal/v533/n7603/full/nature17967.html

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