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 defence (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 defences against infection. Our research has been instrumental in delivering, to clinical trials, both topical antimicrobials and selectively immunomodulatory innate defence 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 often (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.

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)
Type
Exploratory/Developmental Grants Phase II (R33)
Project #
4R33AI098701-03
Application #
8823060
Study Section
No Study Section (in-house review) (NSS)
Program Officer
Xu, Zuoyu
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of British Columbia
Department
Type
DUNS #
City
Vancouver
State
BC
Country
Canada
Zip Code
V6 1Z3
Hilchie, Ashley L; Sharon, Andrew J; Haney, Evan F et al. (2016) Mastoparan is a membranolytic anti-cancer peptide that works synergistically with gemcitabine in a mouse model of mammary carcinoma. Biochim Biophys Acta 1858:3195-3204
Pletzer, Daniel; Coleman, Shannon R; Hancock, Robert Ew (2016) Anti-biofilm peptides as a new weapon in antimicrobial warfare. Curr Opin Microbiol 33:35-40
Mansour, Sarah C; Pletzer, Daniel; de la Fuente-Núñez, César et al. (2016) Bacterial Abscess Formation Is Controlled by the Stringent Stress Response and Can Be Targeted Therapeutically. EBioMedicine 12:219-226
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de la Fuente-Núñez, César; Cardoso, Marlon Henrique; de Souza Cândido, Elizabete et al. (2016) Synthetic antibiofilm peptides. Biochim Biophys Acta 1858:1061-9
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
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
Gill, Erin E; Franco, Octavio L; Hancock, Robert E W (2015) Antibiotic adjuvants: diverse strategies for controlling drug-resistant pathogens. Chem Biol Drug Des 85:56-78
Haney, Evan F; Mansour, Sarah C; Hilchie, Ashley L et al. (2015) High throughput screening methods for assessing antibiofilm and immunomodulatory activities of synthetic peptides. Peptides 71:276-85
de la Fuente-Núñez, César; Mansour, Sarah C; Wang, Zhejun et al. (2014) Anti-Biofilm and Immunomodulatory Activities of Peptides That Inhibit Biofilms Formed by Pathogens Isolated from Cystic Fibrosis Patients. Antibiotics (Basel) 3:509-26

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