Since 1980 the mortality rate due to infectious disease in the United States has doubled. Emerging and reemerging bacterial pathogens are a major cause of the increased mortality and there is an urgent need for new approaches to combat these pathogens. We propose to establish a Center for Excellence in Translational Research that supports five projects organized around a single theme: the development of innovative countermeasures against bacterial pathogens based on targeting the bacterial cell envelope. The Center will leverage the powerful synergies and comprehensive knowledge of seven leading Harvard investigators in the area of bacterial cell envelope biology to establish novel platforms for the production of antibacterial vaccines targeting cell surface carbohydrates and for the discovery of antibacterials. These platforms will be used to develop vaccines for Francisella tularensis, Burkholderia pseudomallei, Vibrio cholerae, and Salmonella typhi among others, and to discover antibiotics that kill antibiotic resistant ESKAPE pathogens, including Staphylococcus aureus, Pseudomonas aeruginosa, and Acinetobacter baumannii, by inhibiting cell envelope targets. One vaccine platform will enable rational design of highly effective glycoconjugate vaccines from pure peptide and oligosaccharide components, while the other will provide technologies to rapidly produce cost-effective cell envelope-based vaccines as countermeasures for unexpected or developing-world epidemics. The antibacterial discovery projects focus on different cell envelope pathways and pathogens, but a cornerstone of all three projects is a highly effective new paradigm for high throughput screening that combines the strengths, while overcoming the weaknesses, of traditional target- and cell-based screening approaches.
We aim to provide as deliverables to development pipelines at least one new vaccine and 3-5 antibacterial compounds that have validated cell envelope targets and demonstrate efficacy in animal models - while simultaneously making significant advances in the underlying science of cell envelope biology. The CETR investigators are leaders in their respective fields and comprise a multidisciplinary team of unusual scientific breadth and accomplishment as well as comprehensive administrative experience since the PI led the highly successful NERCE program. Scientific expertise of the investigators includes immunology, molecular pathogenesis, molecular genetics of both Gram negative and Gram positive organisms, biochemistry/enzymology, glycobiology, synthetic organic chemistry, genomic methods, high throughput screening/follow up chemistry, antibiotic mechanisms of action and resistance, and vaccine development.

Public Health Relevance

There is a desperate need for effective countermeasures against emerging and re-emerging pathogens. Needed countermeasures include vaccines to prevent infection in at-risk populations and antibiotics to overcome potentially lethal treatment-resistant infections. This Center comprises two vaccine development projects and three antibacterial discovery projects organized around the theme of targeting the bacterial cell envelope. It also includes a sophisticated Discovery and Translational Services Core that will facilitate the translation of academic knowledge into effective countermeasures against bacterial pathogens.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-LR-M (J1))
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Schaefer, Michael R
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Harvard University
Schools of Medicine
United States
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Zhang, Ge; Baidin, Vadim; Pahil, Karanbir S et al. (2018) Cell-based screen for discovering lipopolysaccharide biogenesis inhibitors. Proc Natl Acad Sci U S A 115:6834-6839
Sham, Lok-To; Zheng, Sanduo; Yakhnina, Anastasiya A et al. (2018) Loss of specificity variants of WzxC suggest that substrate recognition is coupled with transporter opening in MOP-family flippases. Mol Microbiol 109:633-641
Lee, Wonsik; Do, Truc; Zhang, Ge et al. (2018) Antibiotic Combinations That Enable One-Step, Targeted Mutagenesis of Chromosomal Genes. ACS Infect Dis 4:1007-1018
Fenton, Andrew K; Manuse, Sylvie; Flores-Kim, Josué et al. (2018) Phosphorylation-dependent activation of the cell wall synthase PBP2a in Streptococcus pneumoniae by MacP. Proc Natl Acad Sci U S A 115:2812-2817
Buss, Jackson A; Baidin, Vadim; Welsh, Michael A et al. (2018) A pathway-directed screen for inhibitors of the bacterial cell elongation machinery. Antimicrob Agents Chemother :
Santiago, Marina; Lee, Wonsik; Fayad, Antoine Abou et al. (2018) Genome-wide mutant profiling predicts the mechanism of a Lipid II binding antibiotic. Nat Chem Biol 14:601-608
Baranowski, Catherine; Welsh, Michael A; Sham, Lok-To et al. (2018) Maturing Mycobacterium smegmatis peptidoglycan requires non-canonical crosslinks to maintain shape. Elife 7:
Rohs, Patricia D A; Buss, Jackson; Sim, Sue I et al. (2018) A central role for PBP2 in the activation of peptidoglycan polymerization by the bacterial cell elongation machinery. PLoS Genet 14:e1007726
Vickery, Christopher R; Wood, B McKay; Morris, Heidi G et al. (2018) Reconstitution of Staphylococcus aureus Lipoteichoic Acid Synthase Activity Identifies Congo Red as a Selective Inhibitor. J Am Chem Soc 140:876-879
Bertani, Blake R; Taylor, Rebecca J; Nagy, Emma et al. (2018) A cluster of residues in the lipopolysaccharide exporter that selects substrate variants for transport to the outer membrane. Mol Microbiol 109:541-554

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