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Biological Chemistry

Newfound Antibiotic Is Gargantuan And Unfortunately Deadly

Natural Products: Large macrolactone features a 52-membered ring and overall contains 105 carbon atoms, of which nearly half are chiral centers

by Stephen K. Ritter
March 12, 2015 | A version of this story appeared in Volume 93, Issue 11

Gargantulide A is a big, utterly complex, and fantastic molecule to gaze upon. But the polyketide natural product with promising antibiotic properties is so deadly toxic it will have to be shelved (Org. Lett. 2015, DOI: 10.1021/acs.orglett.5b00068).

An international research team led by William H. Gerwick of the University of California, San Diego, and Mark S. Butler, formerly of MerLion Pharmaceuticals, in Singapore, found gargantulide A in a high-throughput screen of the biochemical effluent of a Streptomyces bacterium. That was the easy part.

More challenging was the team’s effort to elucidate the structure of gargantulide A, which required implementing nearly every conceivable NMR spectroscopy analysis method. The molecule features a 52-membered macrolactone ring and overall contains 105 carbon atoms, of which nearly half are chiral centers. Gerwick praises UCSD team member Jung-Rae Rho’s NMR prowess.

The researchers found that gargantulide A kills pathogenic bacteria such as MRSA and Clostridium difficile. But injecting mice with the compound led to a quick death for the animals. The severe toxicity has precluded any further development of the compound as an antibiotic.

Gargantulide A is “a pretty amazing molecule,” Gerwick says. “Nature still has some surprises for us in terms of novel structures with powerful biological properties.”

Structure of gargantulide A.


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