Title Professor of Pathology Institution Beth Israel Deaconess Medical Center Address Beth Israel Deaconess Medical Center Pathology - Yamins 309 330 Brookline Ave Boston MA 02215
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Mentoring
Available: 12/01/22, Expires: 07/31/27
Antibiotic resistance is a major impediment to successful treatment of patients. Multidrug efflux pumps contribute to broad-spectrum antimicrobial resistance. This mechanism of resistance is particular important in certain pathogen groups like Pseudomonas, Acinetobacter, Burkholderia and Stenotrophomonas, sometimes leaving few if any treatment options.
The goal of this student project is to understand how these efflux pumps function. Based on structural understanding of efflux pumps and cross comparisons among efflux pumps and the known efflux substrates, we will generate hypothesis about mechanisms of specific substrate recognition, and test these hypothesis by directed mutation of the pump amino acid sequence, and then measuring efflux of antibiotics of interest. This is a great project for a several month to a one year commitment as the questions are well defined and will allow the student to generate their own hypotheses and test them. Techniques would include highly efficient directed mutagenesis, structural predictions based on programs such as Pymol, Maestro, and alphafold2 to drive hypothesis generation and interpret results, and minimal inhibitory concentration analysis.
We collaborate extensively with Ed Yu (Case Western Reserve University School of Medcine) who solved the first structure of a bacterial efflux pump, and is a leader in the structural biology of RND efflux pumps of interest. In collaboration with Dr. Yu, we also may also express and isolate the efflux pump proteins, and Dr. Yu's laboratory will solve the structures of the pumps by cryo-EM allowing us to confirm predicted hypotheses related to structure function correlations.
Our long-term goal in underestanding, structure function correlations of efflux pumps is for future design of therapeutics that can inactivate pumps and thereby restore activity of existing antibiotics. Conversely, with a better understanding of pump substrate binding we can apply this knowledge to development of antibiotics that are no longer pump substrates and can then function in pump activated organisms. We are actively interested in design of such antibiotics.
I have had other Harvard Medicla Students in the laboratory, and would welcome involvement of medical students. More information about he laboratory can be found at https://www.kirbylab.org

Research
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R01AI157208
(KIRBY, JAMES E)
Sep 23, 2020 - Aug 31, 2025
Use of De Novo Synthesis Approaches and Structure-guided Design to Optimize Therapeutic Properties of Streptothricin Class Antimicrobials
Role: Principal Investigator
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R01AI154860
(KIRBY, JAMES E)
Aug 20, 2020 - Jul 31, 2024
De Novo Synthesis, and Functional and Structural Characterization of Novel Aminoglycoside Analogues to Bypass Resistance Mechanisms and Optimize Selectivity
Role: Principal Investigator
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R21AI146485
(KIRBY, JAMES E)
May 15, 2019 - Apr 30, 2021
Fusidic acid derivatization to enhance entry into Gram-negative pathogens
Role: Principal Investigator
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R21AI140212
(MANETSCH, ROMAN)
Mar 1, 2019 - Feb 28, 2021
Development of Streptothricin Class Antimicrobials as Novel Therapeutics
Role: Co-Principal Investigator
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R03AI144196
(KIRBY, JAMES E)
Feb 8, 2019 - Jan 31, 2021
Targeted modification of the apramycin 2-deoxystreptamine ring to block aminoglycoside modifying enzyme-based inactivation and enhance potency against multidrug-resistant Gram-negative pathogens
Role: Principal Investigator
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R21AI142040
(KIRBY, JAMES E)
Nov 13, 2018 - Oct 31, 2021
Apramycin scaffold exploration using novel glycochemistry and SAR studies to enhance activity against Acinetobacter baumannii and other multidrug-resistant Gram-negative pathogens
Role: Principal Investigator
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R21AI130434
(KIRBY, JAMES E)
May 15, 2018 - Apr 30, 2021
Microscopy-Based Antimicrobial Susceptibility Testing (MAST)
Role: Principal Investigator
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R33AI119114
(KIRBY, JAMES E)
Jul 1, 2015 - Jun 30, 2021
Plasmid Eviction to Restore Susceptibility in Carbapenem-Resistant Enterobacteriaceae
Role: Principal Investigator
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R21AI119114
(KIRBY, JAMES E)
Jul 1, 2015 - Jun 30, 2017
Plasmid Eviction to Restore Susceptibility in Carbapenem-Resistant Enterobacteriaceae
Role: Principal Investigator
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R21AI112694
(KIRBY, JAMES E)
Jan 1, 2015 - Dec 31, 2016
VALIDATION OF A HIGH THROUGHPUT SCREEN FOR KPC PLASMID EVICTION
Role: Principal Investigator
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R01AI099122
(KIRBY, JAMES E)
Sep 24, 2012 - Aug 31, 2018
Novel Antimicrobials Targeting Bacterial Type IV Secretion Systems
Role: Principal Investigator
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R21AI082264
(KIRBY, JAMES E)
Mar 15, 2010 - Feb 29, 2012
Type IV Secretion System Therapeutics
Role: Principal Investigator
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R21AI076691
(KIRBY, JAMES E)
Apr 1, 2008 - Mar 31, 2011
Non-Antibiotic Selectable Markers for Bacillus Anthracis
Role: Principal Investigator
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R21AI062990
(KIRBY, JAMES E)
Jun 15, 2005 - May 31, 2008
The Basis of Anthrax-Induced Vascular Damage
Role: Principal Investigator
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K08AI001402
(KIRBY, JAMES E)
Jul 1, 1996 - Jun 30, 2001
LEGIONELLA PNEUMOPHILA VIRULENCE FACTORS DEFINED IN VIVO
Role: Principal Investigator

Bibliographic
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