Antibiotic resistance is widespread and increasing, and there is an urgent clinical need for new antimicrobial targets and therapies. The most attractive new targets are those in pathways where inhibitors have an established history of clinical success. We therefore focus on identifying new vulnerabilities in the bacterial cell wall/peptidoglycan (PG) assembly process, the primary target of one of our most successful antibiotic classes, the p-lactams. Our goal is to use chemical screens to identify small molecules with broad-spectrum antibiotic activity and in vivo efficacy. To do so, we will develop """"""""smart"""""""" chemical screens that incorporate pathway-specificity in their readout, taking advantage of knowledge gained from our basic mechanistic studies of PG biogenesis in E. coli In Aim 1, we exploit our discovery of specialized growth conditions that render a highly conserved PG-synthesizing complex called the Rod system simultaneously non-essential and toxic. We will identify inhibitors of this normally essential complex by screening for growth-promoting molecules. The positive readout of this chemical suppressor screen is a tremendous advantage as it automatically eliminates non-specific cytotoxic compounds.
Aim 2 will focus on characterizing an enzymatic activity that has long been thought to be essential for PG synthesis but has eluded researchers for decades. This activity is part ofthe Rod system. Our results will therefore both define a highly attractive new antibiotic target and aid in the characterization of the Rod system inhibitors identified in Aim 1.
Aim 3 describes a new approach to antibiotic discovery. Rather than focusing on small molecules that inhibit essential processes as is traditionally done, we will use our knowledge of the regulatory pathways controlling cell wall degrading enzymes to implement a pathway-directed screen for compounds that aberrantly trigger their activation and induce lysis.
Aim 4 is dedicated to using a novel high-throughput genetic approach in ?. coli and S. aureus to identify new opportunities for applying pathway-directed screens for antibiotics. The most promising compounds identified in our screens will be optimized in collaboration with the Center's Discovery and Translational Service Core. Those with broad-spectrum activity, high potency (MIC <25 pM), and low cytotoxicity (toxic dose >10x MIC) will be further tested for in vivo efficacy by the core. Industry partners will be sought to move effective molecules into a pipeline for the generation of new therapies to treat infections caused by antibiotic-resistant bacteria.
New approaches for antibiotic discovery are sorely needed to develop the next generation of therapies against drug-resistant bacteria. This project is focused on identifying new vulnerabilities in the bacterial cell wall biogenesis pathway to target with antimicrobial agents. The chemical inhibitors of cell wall biogenesis identified will validate new targets and provide lead compounds for the generation of new therapies against multi-drug resistant bacteria.
|Moison, Eileen; Xie, Ran; Zhang, Ge et al. (2017) A Fluorescent Probe Distinguishes between Inhibition of Early and Late Steps of Lipopolysaccharide Biogenesis in Whole Cells. ACS Chem Biol 12:928-932|
|May, Janine M; Owens, Tristan W; Mandler, Michael D et al. (2017) The Antibiotic Novobiocin Binds and Activates the ATPase That Powers Lipopolysaccharide Transport. J Am Chem Soc 139:17221-17224|
|Surana, Neeraj K; Kasper, Dennis L (2017) Moving beyond microbiome-wide associations to causal microbe identification. Nature 552:244-247|
|Matano, Leigh M; Morris, Heidi G; Hesser, Anthony R et al. (2017) Antibiotic That Inhibits the ATPase Activity of an ATP-Binding Cassette Transporter by Binding to a Remote Extracellular Site. J Am Chem Soc 139:10597-10600|
|Pasman, Lesley; Kasper, Dennis L (2017) Building conventions for unconventional lymphocytes. Immunol Rev 279:52-62|
|Pang, Ting; Wang, Xindan; Lim, Hoong Chuin et al. (2017) The nucleoid occlusion factor Noc controls DNA replication initiation in Staphylococcus aureus. PLoS Genet 13:e1006908|
|Hudak, Jason E; Alvarez, David; Skelly, Ashwin et al. (2017) Illuminating vital surface molecules of symbionts in health and disease. Nat Microbiol 2:17099|
|Qiao, Yuan; Srisuknimit, Veerasak; Rubino, Frederick et al. (2017) Lipid II overproduction allows direct assay of transpeptidase inhibition by ?-lactams. Nat Chem Biol 13:793-798|
|Chamakura, Karthik R; Sham, Lok-To; Davis, Rebecca M et al. (2017) A viral protein antibiotic inhibits lipid II flippase activity. Nat Microbiol 2:1480-1484|
|Welsh, Michael A; Taguchi, Atsushi; Schaefer, Kaitlin et al. (2017) Identification of a Functionally Unique Family of Penicillin-Binding Proteins. J Am Chem Soc 139:17727-17730|
Showing the most recent 10 out of 29 publications