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Towards the Translation of Synergistic Phage-Polymyxin Combination Therapy against Pandrug-resistant Klebsiella pneumoniae: A Systems Approach

Award Number: R21AI156766
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: 08/16/2021
PERIOD OF PERFORMANCE END DATE: 07/31/2024

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Towards the Translation of Synergistic Phage-Polymyxin Combination Therapy against Pandrug-resistant Klebsiella pneumoniae: A Systems Approach - Antimicrobial resistance (AMR) has become one of the greatest global threats to human health. Pandrug- resistant (PDR) Klebsiella pneumoniae has been identified by the World Health Organization as one of the 3 top- priority pathogens urgently requiring new treatments. Polymyxins are often used as the last option; however, plasmid-mediated polymyxin resistance highlights the urgency to develop novel therapeutics to treat PDR K. pneumoniae. Bacteriophage (i.e. phage) has recently attracted substantial attention as a promising option to treat PDR bacterial infections; unfortunately, resistance to phage monotherapy in K. pneumoniae can rapidly develop. Optimal phage-antibiotic combinations provide a superior approach; however, there is a significant lack of knowledge on the pharmacokinetics/pharmacodynamics/toxicodynamics (PK/PD/TD) of phage therapy. This situation has severely hindered the optimization of phage therapy against bacterial ‘superbugs’ and limited their clinical utility. Traditional PK/PD/TD plays a critical role in optimizing antibiotic dosage regimens, but lacks systems and mechanistic information. Furthermore, antibiotic PK/PD/TD cannot be easily extrapolated to phage therapy, mainly due to their unique PK, host specificity and self-amplification. As phage-antibiotic synergy also depends on the dynamics of infection and host responses, innovative strategies incorporating systems pharmacology and host-pathogen-phage-antibiotic interactions have the significant potential to optimize their clinical use. Excitingly, we have isolated a number of phages with superior activity against PDR K. pneumoniae, and identified several novel phage-antibiotic combinations (e.g. with polymyxins) that synergistically kill PDR K. pneumoniae in vitro and in animals without any regrowth. Considering the urgent need to optimize phage therapy and minimize resistance to the last-line polymyxins, it is essential to develop superior phage-polymyxin combinations using a systems approach by integrating PK/PD/TD and multi-omics. Therefore, the Specific Aims of this application are: (1) To identify superior synergistic combinations of phage and polymyxin B, and evaluate their PK/PD/TD against PDR K. pneumoniae using in vitro and animal infection models; (2) To elucidate the mechanisms of synergistic bacterial killing by the superior phage-polymyxin combinations and the host- pathogen-phage-polymyxin interactions using correlative multi-omics; and (3) To develop novel QSP models integrating PK/PD/TD and multi-omics data for the superior phage-polymyxin combinations targeting PDR K. pneumoniae, and propose optimal dosage regimens for future clinical trials. Our innovative multi-disciplinary project will generate urgently needed information for rational optimization of novel phage-polymyxin combinations. Importantly, this proposal aligns perfectly with the present NIAID RFA for exploiting phages to kill ‘superbugs’ and responds in a timely manner to the recent 2019 NIAID Antibiotic Resistance Framework to protect global health security.


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: 2025 ( Subtotal = $0 )
2025	2022	MONASH UNIVERSITY	WELLINGTON RD	CLAYTON				AUS	Allergy and Infectious Diseases Research	000	2	2/11/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $150,599 )
2022	2022	MONASH UNIVERSITY	WELLINGTON RD	CLAYTON	VIC			AUS	Allergy and Infectious Diseases Research	002	2	8/8/2022	NON-COMPETING CONTINUATION	$0
2022	2022	MONASH UNIVERSITY	WELLINGTON RD	CLAYTON	VIC			AUS	Allergy and Infectious Diseases Research	001	2	7/21/2022	NON-COMPETING CONTINUATION	$137,249
2022	2021	MONASH UNIVERSITY	WELLINGTON RD	CLAYTON	VIC			AUS	Allergy and Infectious Diseases Research	000	1	11/4/2021	NEW	$13,350
														Subtotal = $150,599

Issue Date FY: 2021 ( Subtotal = $197,381 )
2021	2021	MONASH UNIVERSITY	WELLINGTON RD	CLAYTON	VIC			AUS	Allergy and Infectious Diseases Research	000	1	8/16/2021	NEW	$197,381
														Subtotal = $197,381

Grand Total All Awards = $347,980

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Towards the Translation of Synergistic Phage-Polymyxin Combination Therapy against Pandrug-resistant Klebsiella pneumoniae: A Systems Approach

Award Number: R21AI156766

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: 08/16/2021

PERIOD OF PERFORMANCE END DATE: 07/31/2024

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