SBIR-STTR Award

Rib-X Pharmaceuticals, Inc. has proprietary, high-resolution structural information on how antibiotics bind to the large ribosomal subunit (50S). Using this information in combination with a computational approach that calculates the energetics of RNA-ligand interactions and drug-like properties of these antibiotics, a series of novel compounds were designed and synthesized. One of the compounds was complexed to Haloarcula marismortui 50S ribosomal subunits and solved to 3.0 Angstroms resolution. The position of the analog within the 50S subunit validated our approach and suggested that solving related structures within the series would provide a solid platform to understand how this series of compounds overcomes target-based resistance. To aid in drug design, this proposal seeks to: 1. Determine two additional high resolution structures of compounds complexed with the 50S subunit of Haloarcula marismortui. 2. Determine the minimally-active chemical core in the compound series. 3. Determine the pharmacokinetics of the most promising compound in mice. The overall goal of this work is to identify new chemical entities for the treatment of antibiotic resistant bacterial infections. This is important because the incidence of antimicrobial resistance has increased in hospital and community settings. Therapeutic failures with current agents, extended hospital stays, and the use of increasingly costly and toxic antimicrobials that contribute to healthcare costs is driving the need for new antimicrobial agents that overcome multidrug resistance. Resistance is likely to become worse when patents for widely used, branded antibiotics like Augmentin, Cipro, and Zithromax expire, resulting in widespread use of generic versions of these drugs. The 50S subunit is a highly validated target in that two of the top four oral antibiotics in the US target it (Zithromax and Biaxen); collectively, these two antibiotics account for >$2 billion in annual sales. Further, the most recently approved class of antibiotics, Zyvox, also binds to the 50S. Zyvox is used to treat serious Gram-positive nosocomial infections. Thus, the 50S presents an opportunity to target medical needs and to find new antimicrobials for both community- and hospital-acquired infections.

Thesaurus Terms:
antibacterial agent, chemical structure function, drug design /synthesis /production, pharmacokinetics, ribosome chemical binding, chemical model, computer simulation, drug resistance, mathematical model, molecular dynamics Archaea, laboratory mouse

The specific goal of this proposal is to initiate preclinical studies towards satisfying the requirements for an Investigative New Drug Application (IND) after identifying a compound(s) that could be commercialized and prescribed for the treatment of multidrug-resistant (MDR) Gram-positive hospital-acquired infections. The increased frequency of multidrug resistance in key pathogens has motivated us to employ our structure-based design approach to identify compounds that target multidrug-resistant (MDR) Gram-positive pathogens. For use in nosocomial infections caused by Gram-positive pathogens, a drug must cover Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, and Enterococcus faecium. Coverage of Streptococcus pneumonias (for treatment of patients who are either hospitalized due to community-acquired pneumonia or develop a Gram-positive pneumonia while hospitalized) and other species of staphylococci and enterococci would be highly desirable. To be commercially successful, it would be highly desirable for the drug to have pharmacokinetics commensurate with once or twice daily dosing. For life-threatening infections in the hospital, an IV agent would be needed, ideally followed by an oral formulation of the same drug. Looking ahead, this agent would cover strains that have resistance to macrolides, quinolones, vancomycin, a-lactams, Synercid(r), and Linezolid. In our Phase I application, we set out to identify the active core of a new chemical entity that inhibits protein synthesis in the bacterial cell, determine its 3D structure when complexed to its target (the SOS subunit of the ribosome), and determine basic pharmacokinetics of one compound in this promising series. Having successfully completed all the goals from our Phase I application, we seek in this Phase II proposal to: 1. Determine MIC90 values for compounds with MICs = 5 fg/ml against Gram-positive pathogens in our primary panel. 2. Determine efficacy in relevant animal models of infection. 3. Characterize compounds for potential to cause drug-drug interactions, adverse side-effects, microsomal lability, cytotoxicity, and for their potential to have oral absorption. 4. Characterize the pharmacokinetic profile of compounds in rodent and non-rodent species. 5. Determine how quickly resistance occurs with key compounds. 6. Initiate preclinical studies on a compound that meets acceptable criteria for treatment of nosocomial Gram-positive bacteria. It is expected that these units of work will provide substantial progress toward an IND filing of a compound active against Gram-positive nosocomial pathogens.

Thesaurus Terms:
antibacterial agent, drug screening /evaluation, gram positive bacteria, nosocomial infection Enterococcus, Staphylococcus, Streptococcus pneumoniae, drug resistance, pharmacokinetics laboratory mouse, laboratory rat