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The population genetics of antibiotic resistance in multi-drug environments

Award Number: R01GM081617
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/02/2007
PERIOD OF PERFORMANCE END DATE: 05/31/2020

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The population genetics of antibiotic resistance in multi-drug environments - Project Summary/Abstract The proliferation of antibioticresistant pathogens has increased attention to the use of drug combinations to combat the evolution of resistance. However, while the phenotypic and genotypic evolutionary paths towards multidrug resistance can be constrained by tradeoffs between resistance to one drug and susceptibility to other drugs or the humanhost environment, evolution often circumvents these obstacles. Focusing on both E. coli and clinical species, we will unravel the potential and limits of such approaches for constraining evolution. In Aim 1, using a novel selection device, the MEGAplate, which follows multiple diversifying bacterial lineages as they migrate and evolve on large antibiotic gradient landscapes, we will comprehensively map the repertoire of multimutational paths to highlevel resistance to a range of antibiotics as well as to pairs of antibiotics presenting adaptive tradeoffs. Coupled with wholegenome sequencing and automated highthroughput phenotyping, this device will enable us to identify common and specific adaptive mechanisms, reveal the predictability and further evolutionary potential of each mutational step, and test whether channeling evolution towards “quasi deadend” genotypes can impede longterm adaptation. In Aim 2, we focus on cycling drug pairs presenting reciprocal adaptive tradeoffs and examine vulnerabilities of the approach. Going “beyond the average”, we will construct a deep library of singlestep mutants selected on one of several different antibiotics and test en masse their crossresistance to the other antibiotics. These results will identify rare “escape” mutants which circumvent inherent tradeoffs between resistance to these drugs. Synthetically combining pairs of mutations which individually show resistance to one drug yet sensitivity to the other, we will reveal whether such mutations can interact nonadditively leading to resistance to both drugs. In Aim 3, we examine the effectiveness yet weaknesses of new “selectioninverting” compounds which we recently found to act preferentially against bacteria expressing the tetracycline resistance efflux pump. We will use a microfluidic device to follow single cells while switching between tetracycline and the new compounds, thereby identifying the optimal regime for selection against the pump. We will then systematically mutate the tetracycline pump to identify mutations that escape the tradeoff. Finally, in Aim 4, we focus on the differences between in vitro and in vivo adaptive pathways to identify the evolutionary constraints imposed by the human host environment. We will use longitudinal isolates from clinical outbreaks to identify which of the resistant mutations observed in the lab also appear during pathogen evolution within the human body and which others are in vivo inaccessible. Comparing evolution of pathogens in immunocompetent versus immunosuppressed patients will point to evolutionary constraints imposed by innate immunity. In summary, our proposed research will reveal the genotypic and phenotypic constraints that govern evolutionary pathways towards multidrug resistance, both in the lab and during longterm infection in humans. Our longterm goal is to help design drug regimes that better prevent the emergence of resistance and to develop algorithms which based on the database of observed mutationalpaths will allow genomebased diagnostics of microbial infections that can both predict current resistance profile and anticipate its future evolution.


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: 2020 ( Subtotal = $0 )
2020	2018	TECHNION RESEARCH & DEVELOPMENT FOUNDATION LTD.	TECHNION CITY	HAIFA				ISR	Biomedical Research and Research Training	000	11	7/21/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $216,000 )
2018	2018	TECHNION RESEARCH & DEVELOPMENT FOUNDATION LTD.	TECHNION CITY	HAIFA				ISR	Biomedical Research and Research Training	002	11	5/28/2018	NON-COMPETING CONTINUATION	$216,000
2018	2017	TECHNION RESEARCH & DEVELOPMENT FOUNDATION LTD.	TECHNION CITY	HAIFA				ISR	Biomedical Research and Research Training	000	10	1/9/2018	COMPETING CONTINUATION	-$213,504
2018	2017	TECHNION RESEARCH & DEVELOPMENT FOUNDATION LTD.	TECHNION CITY	HAIFA				ISR	Biomedical Research and Research Training	001	10	1/11/2018	COMPETING CONTINUATION	$213,504
														Subtotal = $216,000

Issue Date FY: 2017 ( Subtotal = $213,504 )
2017	2017	TECHNION RESEARCH & DEVELOPMENT FOUNDATION LTD.	TECHNION CITY	HAIFA				ISR	Biomedical Research and Research Training	000	10	4/28/2017	COMPETING CONTINUATION	$213,504
														Subtotal = $213,504

Issue Date FY: 2015 ( Subtotal = $329,783 )
2015	2015	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	9	6/10/2015	NON-COMPETING CONTINUATION	$329,783
														Subtotal = $329,783

Issue Date FY: 2014 ( Subtotal = $330,051 )
2014	2014	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	8	5/21/2014	NON-COMPETING CONTINUATION	$330,051
														Subtotal = $330,051

Issue Date FY: 2013 ( Subtotal = $318,675 )
2013	2013	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	7	7/15/2013	NON-COMPETING CONTINUATION	$318,675
														Subtotal = $318,675

Issue Date FY: 2012 ( Subtotal = $329,625 )
2012	2012	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	001	6	6/11/2012	COMPETING CONTINUATION	$329,625
2012	2011	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	5	6/10/2012	NON-COMPETING CONTINUATION	$0
														Subtotal = $329,625

Issue Date FY: 2011 ( Subtotal = $315,642 )
2011	2011	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	5	6/20/2011	NON-COMPETING CONTINUATION	$315,642
														Subtotal = $315,642

Issue Date FY: 2010 ( Subtotal = $318,830 )
2010	2010	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	4	3/31/2010	NON-COMPETING CONTINUATION	$318,830
														Subtotal = $318,830

Issue Date FY: 2009 ( Subtotal = $674,202 )
2009	2009	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	3	3/30/2009	NON-COMPETING CONTINUATION	$322,050
2009	2009	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Trans-NIH Recovery Act Research Support	001	3	9/23/2009	SUPPLEMENT FOR EXPANSION	$352,152
														Subtotal = $674,202

Issue Date FY: 2008 ( Subtotal = $321,100 )
2008	2008	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	2	4/21/2008	NON-COMPETING CONTINUATION	$321,100
														Subtotal = $321,100

Issue Date FY: 2007 ( Subtotal = $321,100 )
2007	2007	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	1	7/2/2007	NEW	$321,100
														Subtotal = $321,100

Grand Total All Awards = $3,688,512

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The population genetics of antibiotic resistance in multi-drug environments

Award Number: R01GM081617

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/02/2007

PERIOD OF PERFORMANCE END DATE: 05/31/2020

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