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DISCOVERY OF POLYMYXIN-BASED ANTIBACTERIAL AGENTS ACTIVE AGAINST MULTI-DRUG RESIS

Award Number: R21AI098731
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: 05/04/2012
PERIOD OF PERFORMANCE END DATE: 04/30/2014

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DISCOVERY OF POLYMYXIN-BASED ANTIBACTERIAL AGENTS ACTIVE AGAINST MULTI-DRUG RESIS - DESCRIPTION (provided by applicant): The emergence of multi-drug resistant pathogenic bacteria represents a serious and growing threat to human lives and national healthcare systems. These 'supebugs' now kill 100,000's of people each year and are estimated to add $20bn in healthcare costs in the US. In particular, the expansion of Gram-negative strains such as Klebsiella pneumonia, Escherichia coli, Acinetobacter baumannii and Pseudomonas aeruginosa and the rapidly spreading NDM-1 phenotypes are of grave concern. For many of these Gram-negative infections, colistin (polymyxin E) remains the only option of 'last resort', where the carbapenems are no longer active, and cases of tigecycline resistance have been reported. Aims & Objectives: We aim to produce new antibiotics, based on colistin, that are active against resistant 'super-bugs' and that have better safety profiles than current 'last-resor' antibiotics. The research will deliver novel drug-candidates targeted at resistant pathogenic bacteria, and will also provide a detailed scientific understanding of the origins and mechanisms of antibiotic-induced kidney toxicity (nephrotoxicity).We will develop a detailed understanding of how colistin works to kill bacteria. In the longer term, the assays developed for profiling of nephrotoxicity will prove valuable in all areas of drug research, thus providing tools for both antibiotic-renal and more general drug-renal toxicity screening. The new colistin derivatives will be active against the serious Gram-negative super superbugs and attack both drug-sensitive and drug-resistant strains of the bacteria. Approach & methods: This program will use a world first synthetic method for the rapid synthesis of 1,400 colistin analogs for an unprecedented systematic investigation of structure-activity and structure- toxicity relationships. These novel compounds will be optimized for activity against drug-resistant Gram-negative bacteria, in particular NDM-1 strains, and then evaluated for mode of action, stability, cell toxicity and nephrotoxicity. They will also be profiled for binding to the bacterial membranes and molecular target (Lipid A). This will lead to in vivo proof-of-principle for drug action and pharmacokinetic studies for the selection of compounds for future pre-clinical evaluation.


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: 2013 ( Subtotal = $120,307 )
2013	2013	UNIVERSITY OF QUEENSLAND	ST LUCIA BRISBANE	QUEENSLAND				AUS	Allergy and Infectious Diseases Research	000	2	4/16/2013	EXTENSION WITH OR WITHOUT FUNDS	$120,307
														Subtotal = $120,307

Issue Date FY: 2012 ( Subtotal = $169,931 )
2012	2012	UNIVERSITY OF QUEENSLAND	ST LUCIA BRISBANE	QUEENSLAND				AUS	Allergy and Infectious Diseases Research	000	1	5/3/2012	NEW	$169,931
														Subtotal = $169,931

Grand Total All Awards = $290,238

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DISCOVERY OF POLYMYXIN-BASED ANTIBACTERIAL AGENTS ACTIVE AGAINST MULTI-DRUG RESIS

Award Number: R21AI098731

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: 05/04/2012

PERIOD OF PERFORMANCE END DATE: 04/30/2014

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