German researchers have used the powerful analytical technique of X-ray diffraction to home in on an important metabolic reaction used by all pathogenic bacteria and the malaria parasite. The detailed structure of the IspH enzyme active site they revealed, which resembles a shamrock in shape, and has an Fe-S cluster at its core, could offer a promising new target for novel antibiotics that might stave off bacterial resistance.
More details on the research can be found in my XRD column on SpectroscopyNOW this week. Meanwhile, I asked team leader Michael Groll of the Technische Universität München (TUM), to expand on the implications of the work.
What is the next step now that you’ve characterized the active site?
The structure allows us to perform modeling and so look for attractive ligands and putative inhibitors of the enzyme. Furthermore, we need to understand how substrates access the enzyme, docking and release. It looks like there is a major structural rearrangement, a so-called induced-fit mechanism, between the open and the closed (ligand bound) state of the IspH enzyme.
It would be interesting to get further insights into this mechanism which might allow us to get a comprehensive overview of the catalyzed specific reaction. Since the reaction of the substrate is a reduction, the FeS-cluster in the enzyme gets oxidized, we also need to understand the mechanism of enzymatic reduction of this FeS-cluster.
How might drug targets be developed for this enzyme?
Molecular modeling and high throughput screening (HTS) will be key. It would be important to get structures of various ligands including substrate and product (currently we have only modeled the substrate, which we would like to experimentally verify by the complex structure). These new compounds and structures definitely will serve as lead structures for drug development!
Surely, bacteria will simply evolve resistance to those anyway?
Yes, that can be expected. Nevertheless, it should be mentioned that most bacteria become resistant to drugs, since they create enzymes to metabolize the drug or transport it out of the bacteria — this is nothing new. For Vancomycin, it took more than 7 years to see the first resistant strains. It is definitely worth looking for IspH inhibitors as putative new antibiotics. Moreover, it is an attractive new target, because IspH exists only in bacteria, Plasmodia and some plants, and not animals, which would mean a lower risk of side-effects.
Gräwert, T., Rohdich, F., Span, I., Bacher, A., Eisenreich, W., Eppinger, J., & Groll, M. (2009). Structure of Active IspH Enzyme from Provides Mechanistic Insights into Substrate Reduction Angewandte Chemie International Edition, 48 (31), 5756-5759 DOI: 10.1002/anie.200900548