Identification of new molecular targets and antibiotics as novel strategies against filaria infections: characterization of lipid II biosynthesis in Wolbachia endobacteria

• Antragsteller: Kenneth Pfarr, Ph.D.
• Fachliche Zuordnung: Parasitologie und Biologie der Erreger tropischer Infektionskrankheiten
• Förderung: Förderung von 2008 bis 2016
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 33421847

Wolbachia are essential, obligate endobacteria of disease-causing filarial nematodes. The genome of these cell wall-less endosymbionts is reduced, yet encodes proteins required for the synthesis of the peptidoglycan precursor lipid II, but not enzymes that could link the cell wall glycan subunits. To support the hypothesis that lipid II is required during cell division, we have shown that recombinant Wolbachia proteins and purified Wolbachia membranes make lipid I + II and the pathway is essential for Wolbachia growth. Acyldepsipeptides (TP1, targeting ClpP) and corallopyronin A (Cor, TP9, targeting RNA polymerase) depleted Wolbachia in vitro. Cor was also active in vivo, depleting endobacteria from filarial worms in murine filariasis. Thus, we have identified and patented Cor as a novel antibiotic for development into an antifilarial therapy. In the next funding period, we will characterize the role of lipid II during cell division by localizing the enzymes and lipid II with fluorescence and electron microscopy. The structure of the lipid II pentapeptide will be elucidated by substrate feeding experiments using our new “cell-free” Wolbachia culture and recombinant proteins. Our in vitro, ex vivo and in vivo systems will assay the efficacy of novel antibiotics, e.g. lipopeptides (TP8). The results will clarify the lipid II role in cell division and identify new targets and antibiotics. To lay the groundwork for preclinical studies, Cor activity on different filarial worm stages will be analyzed.

• DFG-Verfahren: Forschungsgruppen
• Teilprojekt zu: FOR 854: Post-genomische Strategien für neue antibiotische Wirkstoffe und Zielstrukturen
• Beteiligte Person: Professor Dr. Achim Hoerauf