Platensimycin On My Mind

Yesterday we posted a Latest News item that heralds a potential new class of antibiotics. This is a topic near and dear to my heart, because I worked on the total synthesis of a potential new antibiotic in graduate school. Of course, my time in grad school also taught me not to trumpet ‘potential new antibiotics’ as the next big wonder drugs, because the molecules in question almost always have yet to be tested in people, a process that seldom goes perfectly smoothly.

There was a slightly different twist to this story that made me think it deserved attention: it seems to be nudging researchers and saying, “Don’t get so caught up in the hoopla of fancy genomics technology that you ignore old antibiotic targets that still need exploring.”

In the study, researchers at GlaxoSmithKline, in collaboration with the Wellcome Trust’s Seeding Drug Discovery Initiative and the U.S. Defense Threat Reduction Agency, found a small molecule that blocks DNA gyrase, or type IIA topoisomerase, in an entirely new way. The molecule was effective against a panel of drug resistant bacteria and revealed new nuances of the gyrase mechanism to boot.

Since the news story discussed revisiting old antibiotic targets, I thought I’d spend some time reminding Haystack readers of a search for a new one. Over the last few years, C&EN has extensively covered the story of platensimycin, a promising antibacterial with an exciting target, first isolated from a South African soil sample.

Here’s an abbreviated platensimycin timeline:

May 2006: Merck researchers report the structure of platensimycin and describe its intriguing activity- it blocks FabF, an enzyme involved in fatty acid synthesis, one that has never before been targeted by antibiotics used in the clinic.

October 2006: K.C. Nicolaou group at Scripps Research Institute reports the first total synthesis of racemic platensimycin, setting the stage for making analogs for exploring its bioactivity.

April 2008: Lisa Jarvis’s C&EN cover story counts platensimycin among the natural product antibiotics in development.

March 2009: Microbiologists report that pathogens can scavenge lipids from their mammalian hosts, suggesting that platensimycin’s target (part of the lipid synthesis pathway) may not be a viable target for an antibiotic, after all.

August 2010: I contacted Merck to ask about the current status of platensimycin. Here is what Dr. Sheo Singh, Merck Research Labs Director of Medicinal Chemistry, who led the discovery team on platensimycin in 2006, had to say: “As part of the merger integration of Merck and Schering-Plough, platensimycin is being evaluated and prioritized along with all the other compounds in the early stage pipeline.”

Author: Carmen Drahl

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1 Comment

  1. Well. Platesimycin is dying, I guess, not to due to whether FabF is a validated target or not, but due to its poor PK properties. You never expect a beozoic acid with a hydrophobic tail serve as an antibiotics.