It is becoming increasingly recognized that the therapy of infectious diseases is facing twin threats. On the one hand antibiotic and antiviral resistance is rising rapidly;on the other there are relatively few novel compounds under development or entering the clinic. One promising set of compounds are the cationic host defense (antimicrobial) peptides, that collectively have anti-biofilm, antimicrobial and immunomodulatory activities and are naturally produced by virtually all complex organisms ranging from plants and insects to humans as a major component of their innate defenses against infection. Our research has been instrumental in delivering, to clinical trials, both topicl antimicrobials and selectively immunomodulatory innate defense regulator (IDR) peptides;however these trials did not explore the full potential of these molecules. Recently we demonstrated that some of these peptides suppress the formation of biofilms by a number of serious Gram negative bacterial infections. Here we are pursuing this strategy as an adjunct to conventional antibiotic therapy. It is particularly relevant since bacteria causing infections ofte (60%) grow as biofilms that are specialized colonial structures that are highly resistant to conventional antibiotics. The objective here is this to suppress biofilm infection by highly resistant and dangerous pathogens, making these infections more susceptible to conventional antibiotics. Our major broad long term objective is thus to create badly needed new approaches to treating infections to overcome antibiotic resistance in the face of a dearth in new antibiotic discovery.
Our Specific Aims, in large part based on preliminary data, are (1) identify peptides with optimized activities that are smaller and resistant to proteases, (2) test synergy with a variety of conventional antibiotics against organisms in the biofilm state, (3) understand the mechanism(s) of anti-biofilm activity and (4) characterize their activity in realistic models of infection. 1

Public Health Relevance

The antibiotic era, stemming from the deployment of penicillin, introduced arguably the most successful medicine of all time, impacting dramatically on life expectancy by decreasing childhood and adult deaths from infections, and enabling complex surgeries, transplantations and cancer chemotherapy. The therapy of bacterial infectious diseases is now under severe threat due to an explosion of multiple antibiotic resistance, and a declining rate of discovery of new antibiotics. This proposal will directly address this serious public health issue by developing novel strategies and drugs to deal with recalcitrant resistant Gram-negative pathogens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI098701-01
Application #
8267449
Study Section
Special Emphasis Panel (ZAI1-NLE-M (J1))
Program Officer
Xu, Zuoyu
Project Start
2012-06-18
Project End
2013-05-31
Budget Start
2012-06-18
Budget End
2013-05-31
Support Year
1
Fiscal Year
2012
Total Cost
$170,239
Indirect Cost
$12,610
Name
University of British Columbia
Department
Type
DUNS #
251949962
City
Vancouver
State
BC
Country
Canada
Zip Code
V6 1-Z3
Zhang, Tian; Wang, Zhejun; Hancock, Robert E W et al. (2016) Treatment of Oral Biofilms by a D-Enantiomeric Peptide. PLoS One 11:e0166997
Cardoso, Marlon H; Ribeiro, Suzana M; Nolasco, Diego O et al. (2016) A polyalanine peptide derived from polar fish with anti-infectious activities. Sci Rep 6:21385
Wang, Zhejun; de la Fuente-Núñez, Cesar; Shen, Ya et al. (2015) Treatment of Oral Multispecies Biofilms by an Anti-Biofilm Peptide. PLoS One 10:e0132512
Hancock, Robert E W (2015) Rethinking the Antibiotic Discovery Paradigm. EBioMedicine 2:629-30
de la Fuente-Núñez, César; Reffuveille, Fany; Mansour, Sarah C et al. (2015) D-enantiomeric peptides that eradicate wild-type and multidrug-resistant biofilms and protect against lethal Pseudomonas aeruginosa infections. Chem Biol 22:196-205
Ribeiro, Suzana Meira; de la Fuente-Núñez, César; Baquir, Beverlie et al. (2015) Antibiofilm peptides increase the susceptibility of carbapenemase-producing Klebsiella pneumoniae clinical isolates to β-lactam antibiotics. Antimicrob Agents Chemother 59:3906-12
Feng, Jinsong; de la Fuente-Núñez, César; Trimble, Michael J et al. (2015) An in situ Raman spectroscopy-based microfluidic "lab-on-a-chip" platform for non-destructive and continuous characterization of Pseudomonas aeruginosa biofilms. Chem Commun (Camb) 51:8966-9
Mansour, Sarah C; de la Fuente-Núñez, César; Hancock, Robert E W (2015) Peptide IDR-1018: modulating the immune system and targeting bacterial biofilms to treat antibiotic-resistant bacterial infections. J Pept Sci 21:323-9
de la Fuente-Núñez, César; Hancock, Robert E W (2015) Using anti-biofilm peptides to treat antibiotic-resistant bacterial infections. Postdoc J 3:1-8
de la Fuente-Núñez, César; Reffuveille, Fany; Haney, Evan F et al. (2014) Broad-spectrum anti-biofilm peptide that targets a cellular stress response. PLoS Pathog 10:e1004152

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