Chemistry matters. Join us to get the news you need.

If you have an ACS member number, please enter it here so we can link this account to your membership. (optional)

ACS values your privacy. By submitting your information, you are gaining access to C&EN and subscribing to our weekly newsletter. We use the information you provide to make your reading experience better, and we will never sell your data to third party members.


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 | 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.”



This article has been sent to the following recipient:

Steve Ritter (March 16, 2015 11:50 AM)
In case anyone is wondering, the largest macrolactones reported so far are the zooxanthellamide Cs, which are a mix of 63-, 64-, and 66-membered ring compounds. It seems gargantulide is the next largest.
Nathan (March 19, 2015 9:45 AM)
I'm just curious to know the specific details of toxicity, if there are any particular moieties in the molecule that are responsible for the toxicity and also what's the bioavailability of such a colossal molecule
Mark Butler (March 24, 2015 10:29 PM)
@ Nathan and @ Robert,

The cell cytotoxicity (displays minimal cell line cytotoxicty and haemolysis) does not match correlate with the toxicity shown in vivo. Perhaps there is some target not expressed in these cell lines or some kind of channel blocking?
Robert Buntrock (March 19, 2015 1:12 PM)
How many chemists does it take to determine a structure? How many NMR methods? I guess only chemists are allowed to make chemistry jokes. :+)

Seriously, it's surprising that this substance is so toxic since it seems to large to meet the criteria of the maximum size of a "small molecule" (900-1000). What are the modes of toxicity and are metabolites the active molecules?
Auntie Markovnikov (March 25, 2015 10:43 AM)
I'm not in the field so I do not know the proposed reasons why, but I do know that antiobiotics do not generally follow Lipinksi's Rules, especially the one about molecular weight.
William Szkrybalo (March 19, 2015 5:31 PM)
One wonders why any organism would spend so much energy to synthesize such a molecule. What purpose does the molecule serve in preserving the organism's evolution?
Mark Butler (March 24, 2015 10:42 PM)
This is an interesting question as this Streptomyces produces gargantulide in large amounts under the culture conditions used without detectable amounts of other secondary metabolites. As gargantulide has antibacterial activity it is likely to be produced for defensive purposes; however, whether it would produce so much compound in the natural environment is not known.
How this Streptomyces devised such a complex compound is a wonder of nature and one of the reasons why people people have such a fascination with natural products.
James Neal-Kababick (September 15, 2015 3:08 PM)
Usually such molecules in plants are secondary metabolites used for defensive purposes and that could be the reason this organism produces it as well. It may cut down on the competition or prevent attack from other organisms. This must have been a festive guy to do circular dichroism and NMR on. Yikes!
aa (December 24, 2015 11:37 AM)
what is the natural product for this structure

Leave A Comment

*Required to comment