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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19AI109764-01
Application #
8641912
Study Section
Special Emphasis Panel (ZAI1-LR-M (J1))
Program Officer
Schaefer, Michael R
Project Start
2014-03-01
Project End
2019-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$4,937,887
Indirect Cost
$1,968,927
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Lorenz, Christian; Dougherty, Thomas J; Lory, Stephen (2016) Transcriptional Responses of Escherichia coli to a Small-Molecule Inhibitor of LolCDE, an Essential Component of the Lipoprotein Transport Pathway. J Bacteriol 198:3162-3175
Markovski, Monica; Bohrhunter, Jessica L; Lupoli, Tania J et al. (2016) Cofactor bypass variants reveal a conformational control mechanism governing cell wall polymerase activity. Proc Natl Acad Sci U S A 113:4788-93
Rajagopal, Mithila; Martin, Melissa J; Santiago, Marina et al. (2016) Multidrug Intrinsic Resistance Factors in Staphylococcus aureus Identified by Profiling Fitness within High-Diversity Transposon Libraries. MBio 7:
Simpson, Brent W; Owens, Tristan W; Orabella, Matthew J et al. (2016) Identification of Residues in the Lipopolysaccharide ABC Transporter That Coordinate ATPase Activity with Extractor Function. MBio 7:
Matano, Leigh M; Morris, Heidi G; Wood, B McKay et al. (2016) Accelerating the discovery of antibacterial compounds using pathway-directed whole cell screening. Bioorg Med Chem 24:6307-6314
Meeske, Alexander J; Riley, Eammon P; Robins, William P et al. (2016) SEDS proteins are a widespread family of bacterial cell wall polymerases. Nature 537:634-638
Pasquina, Lincoln; Santa Maria Jr, John P; McKay Wood, B et al. (2016) A synthetic lethal approach for compound and target identification in Staphylococcus aureus. Nat Chem Biol 12:40-5
Lee, Wonsik; Schaefer, Kaitlin; Qiao, Yuan et al. (2016) The Mechanism of Action of Lysobactin. J Am Chem Soc 138:100-3
Cho, Hongbaek; Wivagg, Carl N; Kapoor, Mrinal et al. (2016) Bacterial cell wall biogenesis is mediated by SEDS and PBP polymerase families functioning semi-autonomously. Nat Microbiol :16172
Meeske, Alexander J; Rodrigues, Christopher D A; Brady, Jacqueline et al. (2016) High-Throughput Genetic Screens Identify a Large and Diverse Collection of New Sporulation Genes in Bacillus subtilis. PLoS Biol 14:e1002341

Showing the most recent 10 out of 17 publications