Due to the increasing development of antibiotic resistances by bacterial pathogens, there is a tremendous need for the development of new antibiotic lead structures. Major causes of concern are hereby Gram-negative bacteria as infections with those bacteria are very difficult to treat. Thus there is a high need to identify and develop new antibiotics that are highly effective and can overcome current resistances.
Albicidin has the potential to be such a compound as it displays remarkable antibacterial activity against various Gram-positive and Gram-negative microorganisms. Initially described as an antibiotic substance derived by the plant pathogenic bacterium Xanthomonas albilineans in 1985 its molecular structure of was determined only recently. Unfortunately, the only low amounts of albicidin obtainable are currently the limiting factors in providing sufficient material for therapeutic usage.
Scientists at TU Berlin now developed a convergent total synthesis route toward albicidin enabling the production in multi gram amounts of albicidin that can be used for further profiling of its drug properties. Within this synthesis route various building blocks where identified that can be synthesises separately. Modifications within these building blocks enable the production of several derivatives with different properties
Those variations in the building blocks of albicidin can provide compounds with relevant antibiotic properties, in particular an antibiotic activity against resistant pathogens.
For more detailed information please see the folllowing publications:
Patent: Albicidine derivatives, their use and synthesis.
Kretz, J., Schubert, V., Pesic, A., Hügelland,, M., Royer, M., Cociancich, S., Kerwat, D., Grätz, S., Süssmuth, R.D.
WO/2014/125075, PCT/EP2014/052922 Internationale Patentanmeldung 2014
Total Synthesis of Albicidin: A Lead Structure from Xanthomonas albilineans for Potent Antibacterial Gyrase Inhibitors.
Kretz, J., Kerwat, D., Schubert, V., Grätz, S., Pesic, A., Semsary, S., Cociancich, S., Royer, M., Süssmuth*, R.D.
Angew. Chem. Int., 2014, 54, 1969-1973
The gyrase inhibitor albicidin consists of p-aminobenzoic acids and cyanoalanine.
Cociancich, S., Pesic, D., Petras, D., Uhlmann, S., Kretz, J., Schubert, V., Vieweg, L., Duplan, S., Marguerettaz, M., Noell, J., Pieretti, I.,
Hügelland, M., Kemper, S., Mainz, A., Rott, P., Royer, M., Süssmuth*, R.D.
Nat. Chem. Biol., 2015, 11, 195-197
The Albicidin resistance factor AlbD is a serine endopeptidase that hydrolyzes unusual oligoaromatic-type peptides.
Vieweg, L., Kretz, J., Pesic, A., Kerwat, D., Grätz, S., Royer M., Cociancich, S., Mainz, A., Süssmuth*, R.D.
J. Am. Chem. Soc. 2015, 137, 7608-7611
The O-carbamoyltransferase Alb15 is responsible for the modification of albicidin.
Petras, D., Kerwat, D., Pesic, A., Hempel, B.F., von Eckardstein, L., Semsary, S., Arasté, J., Marguerettaz, M., Royer, M., Cociancich, S., Süssmuth*, R.D.
ACS Chem. Biol. 2016, 11(5):1198-204
First promising results could demonstrate the possibility to establish albicidin as a novel lead structure for antibacterial drug development with resistance-breaking potential.
- First total synthesis route to the novel antibacterial drug albicidin
- Racemization-free synthesis is convergent and easy to scale up
- Strong antibacterial activity with low MIC values
- Active against quinolone resistant strains
EP, US, CA, CN, JP pending
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