Novel Bacterial Cell Wall Biosynthesis Inhibitors for Biodefense Therapeutics

DESCRIPTION (provided by applicant): There is an urgent need for new classes of antibiotics effective on Bacillus anthracis. The ideal drug to address this need would be a small molecule that acts through inhibition of a novel bacterial-specific target. We have discovered a new class of small molecule inhibitors of MurB the second enzyme in bacterial cell wall biosynthetic pathway. We have validated MurB as a target in B. anthracis using antisense technology developed in SBIR grant 53009. The inhibitors have antibacterial activity against B. anthracis and other Gram-positive pathogens. We have obtained the first high-resolution structure of a MurB enzyme bound to one of these inhibitors. The binding occurs in the highly conserved substrate domain of the enzyme. Because of this substrate mimicry and because other MurB inhibitors described in the literature inhibit several peptidoglycan biosynthesis pathway enzymes, the inhibitors could act on other peptidoglycan biosynthesis pathway enzymes in addition to MurB. We propose to develop new biodefense therapeutics using structure-based drug design on the inhibitor-MurB structure. We will investigate activity of the inhibitors on the first six enzymes in the peptidoglycan biosynthesis pathway simultaneously and if warranted pursue dual-target optimization on the best second target. This research plan creates multiple opportunities to discover promising antibiotic leads and even antibiotics with dual target sites. As compounds are designed, the potential ligand interactions with the multiple sites will be considered, thus multiplying the chances of success and decreasing potential for resistance development. To achieve this, we describe an innovative structure-based drug design process. Once this is achieved, the focus of Phase II work will be to apply our high-throughput structural biology platform to optimize the in vivo properties of the leads. The relevance of this work for public health is that new therapeutics may become available to address the rising danger posed by antibiotic-resistant infections as well as the danger of terrorist use of antibiotic-resistant anthrax.