This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Rib-X Pharmaceuticals, Inc. is an early stage pharmaceutical company whose stated goal is to address the difficulties presented by increasing bacterial resistance against current antibacterial agents by discovering novel chemical classes of anti-infectives that target the ribosome. In order to shorten the drug discovery process, we are employing a structure-based design strategy utilizing high resolution crystal structures of the 50S ribosome from Haloarcula marismortui complexed with small molecule inhibitors. These molecules range from known antibiotic leads, to compounds designed and synthesized in-house based on our previous structural results. The resulting structural information will serve as a guide for further compound designs that aim to increase binding affinity and improve overall drug-like qualities. Given the very large unit cell dimensions and diffraction limits of our 50S crystals, we are constrained to use not only a high intensity synchrotron source for x-rays, but are also limited to the best beam lines in terms of brightness, beam collimation and detector size.
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