The emergence of bacterial strains resistant to most of the current antibacterial agents has a significant negative impact on public health. To combat bacterial resistance, new classes of antibacterial agents are needed that have expanded spectrum that includes the resistant strains. Particularly attractive are new classes of antibacterial drugs that inhibit two or more bacterial targets. The potential benefits of these drugs are increased antibacterial potencies, expanded spectrum and significantly reduced frequencies for the emergence of new resistant strains. The goal of this Phase I SBIR proposal is to demonstrate the feasibility of developing a designed multiple-target ligand (DML). This antibacterial agent will combines the already attractive features of a well validated antibacterial class with a second novel mechanism that extends spectrum into resistant strains. Unlike other antibacterial DMLs, this will be the first example of an antibacterial DML discovered by application of structure-based drug design techniques. This approach should provide low molecular weight drugs with favorable pharmacokinetics. Our background information and preliminary data suggests that the selected target pair is attractive for developing DML antibiotics. A lead series has been identified with enzymatic potency on both targets and with good antibacterial spectrum. The S. aureus enzymes from both targets have been crystallized as complexes with important ligands. The docked structures of the lead DML bound to both targets show a remarkable similarity between the two target binding sites and how the ligand binds to both targets. We describe a plan to provide a novel antibacterial class of DMLs that can kill bacteria by two mechanisms. We will obtain structures of DMLs bound to both targets. Using this structural data, we will design and prepare antibacterial DMLs with potency versus both targets. The mechanism of action for these compounds will be determined and the resistance incidence measured. Compound series with attractive potency, spectrum, selectivity and low resistance incidence will be nominated for a Phase II optimization program to generate clinical compounds with broad spectrum activity that includes many of the problematic multi-resistant bacteria. The goal of this work is develop drugs that can treat a wide range of infections including those that are highly problematic because of bacterial resistance. To accomplish this, we introduce a novel concept of using structure-based drug design to develop drugs that kill bacteria by multiple mechanisms
