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Biochemical and structural analysis of emerging resistance threats in Acinetobacter baumannii

Award Number: R15AI082416
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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¿ DESCRIPTION (provided by applicant): In response to the critical and growing threat posed by microbial antibiotic resistance, the NIAID has made basic research leading to better understanding of resistance factors a top priority. The Gram-negative non-fermenting microbe Acinetobacter baumannii has developed resistance to multiple classes of antibiotics in the last 15-20 years, leading the Center for Disease Control to label it a "serious" domestic threat. While many of the basic resistance mechanisms have been extensively studied, newly emerging mechanisms threaten the dwindling therapeutic options. We plan to study how modifications in three A. baumannii enzyme families are enhancing this organism's ability to destroy (or become insensitive) to our most potent antimicrobial agents including carbapenems, advanced generation cephalosporins and monobactams. Preliminary data in our lab has shown that mutations in OXA-51-like class D ß-lactamases have led to enhanced hydrolytic activity against carbapenems. In our proposed studies we will use mutagenesis, kinetic assays and X-ray crystallography to understand how these variant enzymes lead to stronger enzymatic activity. We will explore similar clinical mutations in the OXA-23 and OXA-24/40 class D ß -lactamase subfamilies, investigating in particular how these mutations affect the breakdown of multiple classes of ß -lactam antibiotics. Lastly, we will study known mutations in one of the key target proteins for ß -lactam antibiotics in Acinetobacter spp: penicillin-binding protein 3 (PBP3). It i likely that these clinical mutations are making PBP3 less sensitive to these antibiotics, and thus making the organism less responsive to treatment. Ultimately, by discovering the structural and mechanistic details of how these enzymes are mutating to become more dangerous, we hope to provide direction for the design of more effective antibiotics and ß-lactamase inhibitors. 1


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 = -$6,389 )
2019	2015	GRAND VALLEY STATE UNIVERSITY	1 CAMPUS DR	ALLENDALE	MI	49401	OTTAWA	USA	Allergy and Infectious Diseases Research	000	3	8/30/2019	COMPETING CONTINUATION	-$6,389
														Subtotal = -$6,389

Issue Date FY: 2015 ( Subtotal = $401,272 )
2015	2015	GRAND VALLEY STATE UNIVERSITY	201 LAKE MICHIGAN HALL	ALLENDALE	MI	49401	OTTAWA	USA	Allergy and Infectious Diseases Research	001	3	4/2/2015	COMPETING CONTINUATION	$401,272
2015	2012	GRAND VALLEY STATE UNIVERSITY	201 LAKE MICHIGAN HALL	ALLENDALE	MI	49401	OTTAWA	USA	Allergy and Infectious Diseases Research	000	2	4/1/2015	COMPETING CONTINUATION	$0
														Subtotal = $401,272

Issue Date FY: 2012 ( Subtotal = $394,210 )
2012	2012	GRAND VALLEY STATE UNIVERSITY	201 LAKE MICHIGAN HALL	ALLENDALE	MI	49401	OTTAWA	USA	Allergy and Infectious Diseases Research	000	2	1/31/2012	COMPETING CONTINUATION	$394,210
														Subtotal = $394,210

Issue Date FY: 2009 ( Subtotal = $195,134 )
2009	2009	GRAND VALLEY STATE UNIVERSITY	201 LAKE MICHIGAN HALL	ALLENDALE	MI	49401	OTTAWA	USA	Allergy and Infectious Diseases Research	000	1	3/9/2009	NEW	$195,134
														Subtotal = $195,134

Grand Total All Awards = $984,227

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Biochemical and structural analysis of emerging resistance threats in Acinetobacter baumannii

Award Number: R15AI082416

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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