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Metronidazole resistance in Bacteroides fragilis: an integrated approach

Award Number: R21AI109545
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: 12/19/2013
PERIOD OF PERFORMANCE END DATE: 11/30/2017

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Metronidazole resistance in Bacteroides fragilis: an integrated approach - DESCRIPTION (provided by applicant): Significance: Bacteroides fragilis (BF), an obligatory anaerobic bacterium that is normally a gut commensal, can become an opportunistic pathogen and cause serious infections. It is the major Bacteroides species isolated from human anaerobic infections (80%). Metronidazole (MET) is among the most commonly used antibiotics against BF. Unfortunately, MET resistance among BF is becoming more prevalent and MET resistant (MET-R) strains have resulted in amputations, sepsis and death. While MET resistance in BF has been canonically ascribed to the presence of the nim gene (coding for the NIM protein which prevents the formation of the toxic MET molecule), our results as well as other reports indicate otherwise and suggest that MET resistance is multifactorial. Innovation: This project seeks to identify mechanisms that confer MET resistance in BF using an integrated approach combining classical genetics, Next Generation Sequencing technology and molecular manipulation to relate function to specific genes. Our lab has become skilled in using these techniques for BF research and has a strong global network of colleagues who will send us clinical MET-R BF isolates. Research strategy: In Aim 1A we will study transcriptome changes among spontaneous, sequential MET-R mutants. In Aim 1B, we will identify gene(s) responsible for MET resistance in a saturated transposon mutant library. The genes identified as likely candidates for involvement in MET resistance will be targeted for molecular manipulation and either deleted or overexpressed, as appropriate (Aim 1C). In Aim 2A, we will study the clinical MET-R isolates with genomic sequencing and RNA-SEQ based transcriptome analysis with subsequent comparisons with genomes and transcriptomes from other clinical and lab isolates. We will also use an unbiased approach to find MET resistance-associated genes by introducing genomic libraries made from clinical MET-R strains into the MET susceptible lab strain, BF638R. In Aim 2C, we will demonstrate functional associations of these genes by molecular manipulation (as in Aim 1C). In Aim 3 we will focus on nim-mediated MET resistance and determine whether certain nim alleles are more likely to confer the high MICs seen in clinically resistant strains (Aim 3A) and whether nim might be transferred between strains via a conjugative transposon mobile element (Aim 3B). Impact: The proposed work will provide important NGS data for the Bacteroides research community and suggest a new integrated approach with which to study this pathogen. The data regarding nim gene activity as well as involvement of other key genes will be used to develop new rapid diagnostic tests for MET resistance. In addition, identifying the multiple factors in MET resistance will provide guidance t drug developers in designing therapy.


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: 2018 ( Subtotal = -$227 )
2018	2015	BRENTWOOD BIOMEDICAL RESEARCH INSTITUTE, INC.	11301 WILLSHIRE BLVD BLDG 114 RM 218	LOS ANGELES	CA	90073	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	2	4/20/2018	NON-COMPETING CONTINUATION	-$227
														Subtotal = -$227

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2015	BRENTWOOD BIOMEDICAL RESEARCH INSTITUTE, INC.	11301 WILLSHIRE BLVD BLDG 114 RM 218	LOS ANGELES	CA	90073	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	2	12/21/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2015 ( Subtotal = $153,750 )
2015	2015	BRENTWOOD BIOMEDICAL RESEARCH INSTITUTE	P.O. BOX 25027	LOS ANGELES	CA	90025	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	2	12/1/2014	NON-COMPETING CONTINUATION	$153,750
														Subtotal = $153,750

Issue Date FY: 2014 ( Subtotal = $184,500 )
2014	2014	BRENTWOOD BIOMEDICAL RESEARCH INSTITUTE	P.O. BOX 25027	LOS ANGELES	CA	90025	LOS ANGELES	USA	Allergy and Infectious Diseases Research	001	1	6/9/2014	NEW	$18,450
2014	2014	BRENTWOOD BIOMEDICAL RESEARCH INSTITUTE	P.O. BOX 25027	LOS ANGELES	CA	90025	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	1	12/19/2013	NEW	$166,050
														Subtotal = $184,500

Grand Total All Awards = $338,023

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Metronidazole resistance in Bacteroides fragilis: an integrated approach

Award Number: R21AI109545

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: 12/19/2013

PERIOD OF PERFORMANCE END DATE: 11/30/2017

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