The ESKAPE pathogens, including Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and Enterobacter species are life- threatening superbugs due to their ability to escape the killing of traditional antibiotics. According to the Centers for Diseas Control and Prevention, these six types of bad bugs cause two thirds of the health care-associated infections, leading to 99,000 deaths annually in the United States. It is stunning that the annual frequency of deaths from Methicillin-resistant Staphylococcus aureus (MRSA) is comparable to those caused by HIV/AIDS. Therefore, there is an urgent need to develop new treatments against superbugs. Naturally occurring antimicrobial peptides are universal host defense molecules that have retained their potency throughout the years. To effectively exploit these interesting compounds, we have been constructing, expanding, and updating the widely used Antimicrobial Peptide Database (APD; http://aps.unmc.edu/AP). This comprehensive database facilitates naming, classification, statistical analysis, search, prediction and design of novel antimicrobials with desired properties. The APD tool has facilitated the research and education in the antimicrobial peptide field and laid a solid basis for this project. Based on our preliminary results, we hypothesize that most critical parameters can be extracted from the APD as a basis for designing and optimizing potent antimicrobial peptides that cause damage on bacterial membranes, leading to bacterial death and augmenting host defense. To test our hypothesis, we have designed the following specific aims: (1) To identify the critical parameters that determine potency of antimicrobial peptides and their mimics based on the APD; (2) To elucidate the critical modulator in antimicrobial peptides that determines mechanism of action and potential bacterial response genes; and (3) To examine the efficacy of database-designed peptides and their mimics against bacterial biofilm infection in vivo and mechanisms of immune modulation. To accomplish these aims, the PI has assembled a strong team that provides complementary expertise needed to understand host-pathogen interactions at the genetic, protein, and structural level as well as peptide-mediated immune responses in vivo using animal models. Because our database-designed compounds represent a novel antimicrobial strategy that effectively attenuated resistant superbugs both in vitro and in vivo, the outcome of this innovative research has great potential in providing potent antimicrobial agents that benefit patients.

Public Health Relevance

The ESKAPE superbugs, including Enteroccus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and Enterobacter species, can escape the action of traditional antibiotics, leading to severe illness and causing 99,000 deaths annually in the United States. It is stunning that the total number of deaths due to MRSA infection alone is comparable to AIDS/HIV mortality rates. Therefore, it is urgent to develop a new generation of antimicrobials. This proposal takes an innovative strategy to develop novel antimicrobial compounds that effectively control these dangerous pathogens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI105147-05
Application #
9589453
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Xu, Zuoyu
Project Start
2014-11-01
Project End
2019-10-31
Budget Start
2018-11-01
Budget End
2019-10-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Nebraska Medical Center
Department
Pathology
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Mishra, Biswajit; Wang, Guangshun (2017) Individual and Combined Effects of Engineered Peptides and Antibiotics on Pseudomonas aeruginosa Biofilms. Pharmaceuticals (Basel) 10:
Dong, Yuxiang; Lushnikova, Tamara; Golla, Radha M et al. (2017) Small molecule mimics of DFTamP1, a database designed anti-Staphylococcal peptide. Bioorg Med Chem 25:864-869
Zarena, D; Mishra, Biswajit; Lushnikova, Tamara et al. (2017) The ? Configuration of the WWW Motif of a Short Trp-Rich Peptide Is Critical for Targeting Bacterial Membranes, Disrupting Preformed Biofilms, and Killing Methicillin-Resistant Staphylococcus aureus. Biochemistry 56:4039-4043
Mishra, Biswajit; Reiling, Scott; Zarena, D et al. (2017) Host defense antimicrobial peptides as antibiotics: design and application strategies. Curr Opin Chem Biol 38:87-96
Mishra, Biswajit; Wang, Guangshun (2017) Titanium surfaces immobilized with the major antimicrobial fragment FK-16 of human cathelicidin LL-37 are potent against multiple antibiotic-resistant bacteria. Biofouling 33:544-555
Mishra, Biswajit; Lushnikova, Tamara; Golla, Radha M et al. (2017) Design and surface immobilization of short anti-biofilm peptides. Acta Biomater 49:316-328
Wang, Xiuqing; Junior, José Carlos Bozelli; Mishra, Biswajit et al. (2017) Arginine-lysine positional swap of the LL-37 peptides reveals evolutional advantages of the native sequence and leads to bacterial probes. Biochim Biophys Acta 1859:1350-1361
Lee, Judy T Y; Wang, Guangshun; Tam, Yu Tong et al. (2016) Membrane-Active Epithelial Keratin 6A Fragments (KAMPs) Are Unique Human Antimicrobial Peptides with a Non-?? Structure. Front Microbiol 7:1799
Mishra, Biswajit; Golla, Radha M; Lau, Kyle et al. (2016) Anti-Staphylococcal Biofilm Effects of Human Cathelicidin Peptides. ACS Med Chem Lett 7:117-21
Wang, Guangshun; Li, Xia; Wang, Zhe (2016) APD3: the antimicrobial peptide database as a tool for research and education. Nucleic Acids Res 44:D1087-93

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