Targeted Modification of Membrane Lipids Project Summary The lipid composition of membranes has critical ramifications in biology. It has been long known that bacterial and mammalian cells harbor a different set of lipids in their membranes. While a mammalian cell membrane is largely composed of zwitterionic lipids, bacterial cells typically display anionic lipids in large quantities. Taking advantage of this difference, many organisms have evolved cationic host defense peptides (HDPs), which serve as the frontline of the innate immunity to fend off invading bacterial pathogens. For example, human neutrophils rely on cationic defensins for bacterial cell killing and clearance. To acquire resistance against cationic HDPs, selected bacterial species synthesize the lipid Lys-PG, which carries a net positive charge. We hypothesize that synthetic molecules that bind Lys-PG and consequently mask its net charge will re-sensitize the bacterial cells to killing by HDPs. To test the hypothesis, we will develop synthetic modifiers of Lys-PG by introducing reversible covalent warheads into well-structured scaffolds. Further we will test the efficacy of Lys-PG modification in vitro and in mouse infection models.
The specific aims are: 1) we will use a known, foldable cyclic peptide scaffold to assemble multiple side chains for Lys-PG modification. Computational modeling will be integrated with experimental characterization to optimize for Lys-PG binding; 2) we will develop potent and specific modifiers of Lys-PG by screening novel bicyclic peptide libraries. This part of the proposal will be based on a powerful peptide bicyclization strategy recently developed by our group; 3) the Lys-PG modifiers developed in 1) and 2) will be tested for their capability to potentiate the bactericidal activity of several HDPs and neutrophils. Their efficacy to facilitate bacterial clearance will be further examined in mouse models of infection. With success, the proposed work will yield a novel strategy to fight against the drug-resistance strains of bacterial pathogens. Although the proposed work focuses on Lys-PG, the methodology developed here should be extendable to other lipid modifications of biological significance.

Public Health Relevance

Targeted Modification of Membrane Lipids Project Narrative Antibiotic resistance of pathogenic bacteria poses a serious challenge to our society and calls for novel strategies to counteract the mechanisms of drug resistance. This application seeks to develop synthetic molecules that specifically modify the bacterial lipid Lys-PG, the expression of which allows bacteria to evade the host immune system by gaining resistance to host defense peptides (HDPs). Specific Lys-PG modifiers are expected to re-sensitize the bacterial cells to clearance by host immunity, thus providing a novel strategy to treat HDP-resistant pathogens.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM102735-07
Application #
9729734
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Fabian, Miles
Project Start
2012-09-01
Project End
2022-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
7
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Boston College
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
045896339
City
Chestnut Hill
State
MA
Country
United States
Zip Code
02467
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Cambray, Samantha; Bandyopadhyay, Anupam; Gao, Jianmin (2017) Fluorogenic diazaborine formation of semicarbazide with designed coumarin derivatives. Chem Commun (Camb) 53:12532-12535
Bandyopadhyay, Anupam; Cambray, Samantha; Gao, Jianmin (2017) Fast Diazaborine Formation of Semicarbazide Enables Facile Labeling of Bacterial Pathogens. J Am Chem Soc 139:871-878
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Bandyopadhyay, Anupam; Cambray, Samantha; Gao, Jianmin (2016) Fast and selective labeling of N-terminal cysteines at neutral pH via thiazolidino boronate formation. Chem Sci 7:4589-4593
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Bandyopadhyay, Anupam; Gao, Jianmin (2016) Targeting biomolecules with reversible covalent chemistry. Curr Opin Chem Biol 34:110-116
Bandyopadhyay, Anupam; Gao, Jianmin (2016) Iminoboronate-Based Peptide Cyclization That Responds to pH, Oxidation, and Small Molecule Modulators. J Am Chem Soc 138:2098-101
Bandyopadhyay, Anupam; McCarthy, Kelly A; Kelly, Michael A et al. (2015) Targeting bacteria via iminoboronate chemistry of amine-presenting lipids. Nat Commun 6:6561
Bandyopadhyay, Anupam; Gao, Jianmin (2015) Iminoboronate Formation Leads to Fast and Reversible Conjugation Chemistry of ?-Nucleophiles at Neutral pH. Chemistry 21:14748-52

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