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New Tricks for 'Old' Drugs: PK/PD of Polymyxin Nonantibiotic Combinations

Award Number: R01AI111965
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2014
PERIOD OF PERFORMANCE END DATE: 03/31/2019

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New Tricks for 'Old' Drugs: PK/PD of Polymyxin Nonantibiotic Combinations - DESCRIPTION (provided by applicant): As highlighted in the 'Bad Bugs, No Drugs' campaign by the Infectious Diseases Society of America, "There simply aren't enough new drugs in the pharmaceutical pipeline to keep pace with drug-resistant bacterial infections, so-called 'superbugs'." Numerous hospitals worldwide have experienced outbreaks caused by multidrug-resistant (MDR) Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae, three of the 6 top-priority dangerous "ESKAPE" pathogens that require the most urgent attention to discover new antibiotics. Sadly, no novel antibiotics against these Gram-negative 'superbugs' will be available for many years to come. Polymyxins (i.e. polymyxin B and colistin) are now being used as the last-line therapy for these very problematic MDR pathogens. Most unfortunately, the emergence of polymyxin resistance has been increasingly reported recently. In essence, resistance to polymyxins implies a total lack of antibiotics for treatment of life-threatening infections caused by these pandrug-resistant (PDR) Gram-negative bacteria. Research Design: This project will apply systems pharmacology to antibiotic pharmacokinetics/pharmacodynamics (PK/PD) to identify novel polymyxin combinations with FDA-approved nonantibiotic drugs against PDR P. aeruginosa, A. baumannii and K. pneumoniae. Our over-arching hypothesis is that the identified polymyxin-nonantibiotic combinations will synergistically kill Gram-negative 'superbugs' with minimal development of resistance, and integration of systems pharmacology with antimicrobial PK/PD modeling will elucidate the underlying mechanism(s) of the synergistic interaction between host-pathogen-drug. Our specific aims are to: (1) Identify novel polymyxin-nonantibiotic combinations against pandrug-resistant P. aeruginosa, A. baumannii and K. pneumoniae; (2) Investigate the in vitro PK/PD of active polymyxin-nonantibiotic combinations; (3) Evaluate the synergistic killing and suppression of polymyxin resistance by the active combinations over 2-week treatment using hollow fiber infection model and conduct omics studies; (4) Demonstrate proof-of-concept for the most active combinations using mouse infection models and conduct integrated omics studies to understand the host-pathogen-drug interactions; and (5) Conduct systems pharmacology network analysis and PK/PD mathematical modeling on the polymyxin- nonantibiotic combinations. Transcriptomics, proteomics and metabolomics will be utilized to investigate the interaction between host, pathogen and drug. Together, these studies will identify the best polymyxin-nonantibiotic combination (plus one backup) for further pharmacological evaluations. Significance: This project holds great promise for development of novel polymyxin combinations. As all drugs have already been approved by FDA, our multi-disciplinary approach will provide a fast-track and cost-effective solution to combat these very problematic Gram-negative 'superbugs'. Overall, this project targets the urgent global unmet medical need, lack of new antibiotics.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2018	MONASH UNIVERSITY	WELLINGTON RD	CLAYTON	VIC	3168		AUS	Allergy and Infectious Diseases Research	000	5	8/27/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $819,605 )
2018	2018	MONASH UNIVERSITY	WELLINGTON RD	CLAYTON	VIC	3168		AUS	Allergy and Infectious Diseases Research	000	5	5/4/2018	NON-COMPETING CONTINUATION	$819,605
														Subtotal = $819,605

Issue Date FY: 2017 ( Subtotal = $855,749 )
2017	2017	MONASH UNIVERSITY	WELLINGTON RD	CLAYTON	VIC	3168		AUS	Allergy and Infectious Diseases Research	000	4	3/22/2017	NON-COMPETING CONTINUATION	$855,749
														Subtotal = $855,749

Issue Date FY: 2016 ( Subtotal = $874,635 )
2016	2016	MONASH UNIVERSITY	1 WELLINGTON ROAD	CLAYTON				AUS	Allergy and Infectious Diseases Research	000	3	3/17/2016	NON-COMPETING CONTINUATION	$874,635
														Subtotal = $874,635

Issue Date FY: 2015 ( Subtotal = $893,305 )
2015	2015	MONASH UNIVERSITY	1 WELLINGTON ROAD	CLAYTON				AUS	Allergy and Infectious Diseases Research	000	2	3/18/2015	NON-COMPETING CONTINUATION	$893,305
														Subtotal = $893,305

Issue Date FY: 2014 ( Subtotal = $905,775 )
2014	2014	MONASH UNIVERSITY	1 WELLINGTON ROAD	CLAYTON				AUS	Allergy and Infectious Diseases Research	000	1	3/18/2014	NEW	$905,775
														Subtotal = $905,775

Grand Total All Awards = $4,349,069

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New Tricks for 'Old' Drugs: PK/PD of Polymyxin Nonantibiotic Combinations

Award Number: R01AI111965

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2014

PERIOD OF PERFORMANCE END DATE: 03/31/2019

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