Deciphering small molecules as virulence factors by the bacterial sugarcane pathogen Xanthomonas albilineans

• Applicant: Professor Dr. Roderich D. Süßmuth
• Subject Area: Biological and Biomimetic Chemistry
• Term: from 2013 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 236361684

• Final Report Year: 2016

Final Report Abstract

Xanthomonads are exclusively Gram-negative bacteria that are pathogenic for a variety of plant species of ornamental or agronomical interest. The sugarcane-invading plant pathogen Xanthomonas albilineans is known to occupy the xylem vessels of sugarcane leaves thereby causing the white foliar stripe symptom which leads to the leaf scald disease. X. albilineans has a unique position among the Xanthomonads as the bacterium exhibits distinctive pathogenic mechanisms, ecology and taxonomy caused by significant erosion of its genome. One particular pathogenic mechanism of X. albilineans is the production of a variety of small phytotoxic molecules named albicidins, which are potent DNA gyrase inhibitors that show a broad activity against Gram-negative and Gram-positive bacteria. Albicidin was first described in 1985 by Birch and Patil but its structural features and biosynthetic mechanism remained unknown until recently. In cooperation with the group of Monique Royer from the CIRAD institute in Montpellier, the polyaromatic oligopeptide structure of β-albicidin was elucidated and revealed that the antibiotic is mainly composed of p-aminobenzoic acids. The unravelling of its structure in 2015 paved the way for the development of a convergent total chemical synthesis route in our group which provided milligram amounts of albicidin. Based on in vitro studies, further insights into the biosynthetic machinery were achieved allowing for a deeper understanding of essential steps in the PKS/NRPS hybrid driven biosynthetic pathway. These findings will facilitate the identification of new non-ribosomally synthesized peptides in the genus of Xanthomas species and will strongly promote the analysis of other, less understood NRPS biosynthetic clusters including the ones responsible for the synthesis of the peptides Metacol A, B and C. The high potential and importance of these findings become clear when looking at the simultaneous publications of other quite similar DNA gyrase inhibitor molecules of nonribosomal origin isolated from Cystobacter spec. These were found to be also composed of p-aminobenzoic acids and were named cystobactamides. The new class of promising DNA gyrase inhibitors with a new way of action may overcome the problem of omnipotent bacterial resistance mechanisms and may pave the way for new and highly potent antibiotics.

Publications

• 2015. The albicidin resistance factor AlbD is a serine endopeptidase that hydrolyzes unusual oligoaromatic-type peptides. J Am Chem Soc. 137:7608-7611
  L. Vieweg, J. Kretz, A. Pesic, D. Kerwat, S. Grätz, M. Royer, S. Cociancich, A. Mainz, R.D. Süssmuth
  
• 2015. The gyrase inhibitor albicidin consists of p-aminobenzoic acids and cyanoalanine. Nat Chem Biol. 11:195-197
  S. Cociancich, A. Pesic, D. Petras, S. Uhlmann, J. Kretz, V. Schubert, L. Vieweg, S. Duplan, M. Marguerettaz, J. Noëll, I. Pieretti, M. Hügelland, S. Kemper, A. Mainz, P. Rott, M. Royer, R.D. Süssmuth
  
• 2015. Total synthesis of albicidin: a lead structure from Xanthomonas albilineans for potent antibacterial gyrase inhibitors. Angew Chem Int Ed Engl. 54:1969-1973
  J. Kretz, D. Kerwat, V. Schubert, S. Grätz, A. Pesic, S. Semsary, S. Cociancich, M. Royer, R.D. Süssmuth
  
• 2015. What makes Xanthomonas albilineans unique amongst xanthomonads? Front. Plant Sci. 6:289
  I. Pieretti, A. Pesic, D. Petras, M. Royer, R.D. Süssmuth, S. Cociancich
  
• 2016. The O-carbamoyl-transferase Alb15 is responsible for the modification of albicidin. ACS Chem Biol.
  D. Petras, D. Kerwat, A. Pesic, B.F. Hempel, L. von Eckardstein, S. Semsary, J. Arasté, M. Marguerettaz, M. Royer, S. Cociancich, R.D. Süssmuth