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Jun 09, 2016
 |  BC Innovations  |  Tools & Techniques

Building a better haystack

How Macrolide's chemistry platform could accelerate antibiotics innovation

A year after raising $22 million in a series A round, Macrolide Pharmaceuticals Inc. has disclosed details of how its antibiotic discovery platform is creating a library of compounds with greater structural diversity than was previously possible - starting with eight simple building blocks. The company has created over 650 macrolides, including several with potent activity against Gram-negative pathogens as well as Gram-positive bacteria, the type of bug the antibiotic class has traditionally been most effective against.

CEO Lawrence Miller told BioCentury the company's primary focus is on compounds against multidrug-resistant Gram-negative infections, and it expects to choose a clinical candidate in 2017. "While we're not there yet, we certainly already have better activity than any other macrolide that's ever been published."

Macrolide spun out of Harvard University in February of 2015 after a year and a half in its Blavatnik Biomedical Accelerator, and having secured funding from SR One, Roche Ventures, Novartis Venture Fund and Gurnet Point Capital.

The premise was to rethink how macrolide antibiotics are made, and move away from the practice that has dominated for 60 years of starting with erythromycin, and using a series of increasingly complex steps to modify its functional groups. Traditionally, erythromycin has been generated by fermentation, and then put through procedures for chemical modification - a process dubbed "semisynthesis."

Andrew Myers, co-founder and SAB chairman of Macrolide and professor of chemistry and biology at Harvard, told BioCentury that only a handful of useful drugs have been derived from erythromycin, because the molecule is highly problematic as a starting point.

"Even to an experienced organic chemist, that's a daunting structure," he said. "There's a lot of stereochemistry in the dense array of functional groups around it. The fact that it's a large ring brings its own challenges to synthesis."

Instead, the researchers thought they could simplify the problem by building a modular system that uses a small lineup of relatively simple chemical structures, each of which can be modified separately before assembly into the larger structure, to generate a diverse array of erythromycin analogs on a platform rapid enough to keep pace with the emergence of resistant bacteria.

Last month in Nature, Myers and his Harvard group published details of the platform - the first fully synthetic pathway for creating macrolides - and showed it can generate large numbers of compounds with activity against drug-resistant Gram-positive or Gram-negative bacteria.

"This platform can create orders of magnitude greater structural diversity than is possible through semisynthesis," said Myers.

Paul Reider, professor in the Department of Chemistry at Princeton University and former industry executive, agreed that the platform could make a major impact on the field. "This is the first real breakthrough in macrolide synthesis in over 30 years," he said. "One can now take the privileged scaffold that nature's provided in...

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