Effect of tubulin isoform composition on microtubule dynamics, mechanics, and druggability

• Applicant: Professorin Dr. Simone Reber
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens ; Biochemistry ; Biophysics
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 517962743

The highly dynamic microtubule cytoskeleton plays an essential role in cell division, motility and structural integrity of malarial parasites. Consistent with this vital role, microtubule-disruptive drugs have great potential as anti-malarial agents. However, the development of parasite-specific tubulin drugs has been held back by the lack of purified, functional parasite tubulin and no new class of anti-malarials has been introduced into clinical practice since 1996. Recently, my lab succeeded in the purification and characterisation of assembly-competent P. falciparum tubulin, the reconstitution of P. falciparum microtubule dynamics in vitro, and the identification of compounds that selectively disrupt protozoan microtubule growth without affecting human microtubules. These technological advances put us in the unique position to reconstitute parasite cytoskeletal systems from purified components (1) to quantitatively study P. falciparum microtubule dynamics and mechanics in vitro and (2) to identify novel parasite-specific microtubule-disruptive drugs. (1) Throughout its complex life cycle P. falciparum adapts an amazing variety of cellular morphologies that rely on microtubule structures to enable motility and invasion, to organise cell division, and to withstand diverse environmental forces. How microtubule structure, dynamics and mechanics are affected by tubulin biochemistry and how these adapt to changing ambient temperatures remains largely unknown. Therefore, one aim of this proposal is to gain a mechanistic understanding of microtubule dynamics and mechanics as a function of tubulin isoform composition and temperature. This will allow us to uncover intrinsic isoform-specific adaptation of microtubule-dependent processes to temperatures that differ by 10°C in human and mosquito hosts. (2) Microtubules are excellent candidates for novel anti-malarial drugs. Yet the development of parasite-specific tubulin drugs has been held back by the lack of purified, functional parasite tubulin. Now that we have overcome this major obstacle in the field, the second aim of this proposal is to develop an unbiased, bottom-up, and target-based screen for Plasmodium-specific microtubule-disruptive drugs with the great potential to identify novel frontline anti-malarials. Tying these two aims together, understanding Plasmodium’s fundamental cell biology with a direct mechanistic link to microtubule disruptive drugs, presents a powerful approach in translating basic biology into the realm of drug discovery and infection biology of a clinically relevant pathogen.

• DFG Programme: Research Grants
• International Connection: Australia, United Kingdom, USA
• Cooperation Partners: Professor Dr. Hendrik Luesch; Professorin Dr. Carolyn Moores; Professor Dr. Kevin Saliba