@Real_Dr_Kessler synthesis was rather straightforward and fun since we just had to dimerize the precursors... but being in the way-beyond-Ro5 space (MW > 2000) is not so fun when trying to optimize PK properties 🥲
The second half of our homo-BacPROTAC story is now out in @CellCellPress (even before the other half is accepted)! @DHoi93 walks you through the awesome biology behind this study.
Huge thanks to everyone involved @clausen_lab @ChemHaWei@SchmiedelVolker@somrajguha03 & many more
Excited to share our recent work from the @clausen_lab published in @CellPressNews as part 2 of the BacPROTAC story. Here we use targeted protein degradation as an antibiotics strategy to induce self-elimination of essential mycobacterial Clp proteins. https://t.co/8AqzNw7tSY
"BacPROTAC" ist unser "Stichwort des Monats"!
— Ein Team um @clausen_lab (@IMPvienna) & Markus Kaiser (@unidue) übertrug das Konzept des PROTAC-intiierten Proteinabbaus auf Bakterien – und macht damit die Entwicklung neuartiger #Antibiotika möglich … 👉 https://t.co/MXYUMaZVRO
@agrossfield @leslievosshall @HHMINEWS @ardemp https://t.co/lvTfovGBrw will turn any doi into a 6-letter one. saw it once in a talk and it just makes sense
@rs_mito Probably nothing. The cyclomarins are highly selective for mycobacterial ClpC1, we don't even see any effects on other gram-positive or gram-negative bacteria
I’m excited to share our work on the development of bacterial PROTACs acting against Mycobacterium tuberculosis :) Our "homo-BacPROTACs" are able to kill drug-resistant Mtb by inducing the degradation of ClpC1, an essential protein in mycobacteria.
https://t.co/89VPJSNTNv
This is the first time that TPD and the BacPROTAC concept have been used to construct antibiotics. It’s a totally new way of killing bacteria. Big thanks go out to everyone involved and the great teams at
@Saar_Uni, @Boehringer, @IMPvienna. @clausen_lab @somrajguha03@ChemHaWei
In an SAR study of a library of homo-BacPROTACs, we investigated their solubility, permeability, binding and antibacterial properties. These findings pave the way for further improvements on the way to make BacPROTACs feasible as drugs against TB.
Upon dimerization, we observed a jump in MIC against Mtb by one order of magnitude! The degradation of the target protein leads to an efficient killing of the bacteria. It even kills multi-drug-resistant Mtb and those residing in macrophages.
Guiding you through the paper:
We connected two cyclomarin units using click chemistry or olefin metathesis to make BacPROTACs that hijack the unfoldase ClpC1 and cause it to be degraded by its own associated protease ClpP1P2.