The Lego Game Of Macrolide Antibiotics

The Lego Game Of Macrolide Antibiotics

By Siwei Zhang

What Are Semisynthetic Antibiotics?

Since Alexander Fleming first discovered penicillin in his small laboratory at St. Mary’s Hospital, Paddington, London in 1928, the research, development, and manufacture of antibiotics has been extensively associated with fermentation products from a wide range of different microorganisms, as well as chemical modifications of the structurally complex chemicals that followed. The combined process of fermentation and ensued chemical modification has been known as semisynthesis, which has been proven for its efficiency and versatility during the last 70 years of antibody applications.

Regrettably enough, both medical professionals as well as the social mass are aware that there is a severe reduction in the efficiency of antibiotics, since bacterial resistance against these semisynthetic compounds has developed significantly in past years, through a combination of natural selection and mutation that has been further boosted partly due to the abuse of antibiotics. Hence, new routes on antibiotic development that are not restrained by the limiting products from the fermentation step (precursors), are highly desired.

A New Way Of Making Macrolide Antibiotics: The Lego Way

In the May 19, 2016 issue of Nature, Seiple et al. presented a practical, fully synthetic route to generate macrolide antibiotics through the simple chemical assembly of certain building blocks, which not only greatly simplified the antibiotic making process but, more importantly, allowed the synthesis of diverse structures that are not accessible by traditional semisynthetic routes.

Macrolides, as their name implies, are organic compounds that consist of a large macrocyclic lactone ring, to which additional modifications, such as sugar-derivatives cladinose and desoamine, can be attached and therefore turn them to polyketides with antibiotic or antifungal activities. One of the most common known macrolides is probably erythromycin, a fermentation product that was initially found in soil samples from Philippine and approved by the FDA in 1952. Since then, several derivatives have been developed, with the most recent cases cethromycin and solithromycin, which are currently under clinical trials. However, extensive modification steps (in the case of solithromycin, 16 steps are involved) are required to obtain the derivatives from the initial fermentation step that produces erythromycin from Saccharopolyspora erythraea, which has to be performed in the scale of several tons and renders the semisynthesis process highly inefficient. Moreover, not all the members of the lactone ring can be effectively modified in the naturally-fermented erythromycin without destroying the lactone ring, which serves as the pivotal function for the antibiotic characteristics of erythromycin-derivatives.

In simple terms, we can make the new, fully-synthetic route developed by the authors as an analogy of Lego block building. Instead of having the large, fragile macrocyclic lactone ring at the first place and making modifications on the rings, smaller molecules with their modifications, such as sugar-derivatives, aromatic-derivatives, or amides, have been synthesised. Thus, the last step will be the assembly of the macrocyclic lactone ring.

Advantages and Possibilities

This unconventional method would not only enable a much higher versatility in designing the modifier groups, but, very importantly, through the varying of different building blocks, a kaleidoscope of all-new macrolide antibiotics can be generated quickly in this way with much higher efficiency in raw material utilisation. Indeed, the authors have demonstrated that they are able to generate more than 300 different macrolide analogues in a very short period. Moreover, the antibiotic activity screen of the over 300 macrolides synthesised displayed very strong potential against a panel of clinical pathogens.

In a business perspective, the key takeaway message from this breakthrough technology will be the huge potential in licencing the collection of building blocks, rather than the end-product of macrolide antibiotics. The building block library, which is estimated to be of approximately 500 molecules in size, is expected to grow exponentially. In comparison to the small-molecule libraries owned by major pharmaceutical companies (such as AstraZeneca or Roche), which is usually at the size of several hundreds of thousands, early takeover of the licencing on the patent and manufacture of this building block library at its nascent stage should endorse and secure a stable and long-term revenue for any venture capitals interested in it, especially as we see the declining effectiveness of traditional antibiotics.


A platform for the discovery of new macrolide antibiotics, Nature 533, 338–345 (19 May 2016) doi:10.1038/nature17967

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