50S RIBOSOMAL SUBUNIT IN COMPLEX WITH NOVEL INHIBITORS OF PROTEIN SYNTHESIS

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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 goal is to address the medical difficulties presented by increasing bacterial resistance against current antibacterial agents by developing novel chemical classes of anti-infective molecules that target the ribosome. The medical need for new drugs that circumvent established antibiotic resistance mechanisms in bacteria is dire, with many common drug classes such as penicillins and macrolides having high levels of community resistance in many parts of the world. Though many antibiotics target other aspects of the bacterial life cycle, those that bind to the translational apparatus constitute a majority of use. The central player in translation is the ribosome, a 2.5MDa macromolecular complex that uniquely catalyzes the synthesis of proteins in all organisms. As a universal and essential polymerase, it has been the target of many antibiotics, both natural and synthetic. Bacterial ribosomes are composed of a large 50S (1.5 MDa) and a small 30S (1.0MDa) subunit each with complementary activities. In recent years, the three-dimensional structure of the 50S subunit from H. marismortui has been solved to 2.4 ¿ resolution using x-ray crystallographic methods. In order to shorten the drug discovery process, we employ a structure-based design strategy that utilizes high resolution crystal structures of the 50S ribosome from the archaeal Haloarcula marismortui, complexed with small molecule inhibitors. Given the very large unit cell dimensions of our archeal and eubacterial 50S crystals, we are constrained to use not only a high intensity synchrotron source for x-rays, but also the best beamlines in terms of brightness, beam collimation and detector size.