The primary objective of this research initiative is to use siderophore-antibiotic conjugates based on native siderophore platforms to deliver antibacterial cargo to Gram-negative bacterial pathogens and pathobionts on the basis of siderophore receptor expression and the molecular recognition that occurs between a native siderophore and its receptor(s). Iron is an essential nutrient for almost all human pathogens, and siderophores are small-molecule iron chelators and virulence factors produced by bacteria for acquiring this essential nutrient in the vertebrate host. We hypothesize that the exquisite interactions between native siderophores and dedicated siderophore receptors allow siderophore-appended antibiotics to be directed to select groups of bacterial pathogens, resulting in targeted antibiotic delivery. This approach allows for species- and strain- specific targeting of antibiotics to select pathogens and pathobionts on the basis of siderophore receptor expression. We address this hypothesis by investigating enterobactin and salmochelins, siderophores produced by enteric Gram-negative bacteria, including Escherichia coli and non-typhoidal Salmonella.
In Aim 1, we will expand upon our preliminary results on enterobactin- and salmochelin-mediated delivery of the ?- lactam antibiotics ampicillin (Amp) and amoxicillin (Amx) to the periplasm of Escherichia coli and perform in vitro studies with E. coli and Salmonella to address the uptake and antibacterial mechanisms of these compounds.
In Aim 2, we will perform animal model studies and determine whether administration of the siderophore-?-lactam conjugates affects the composition of the commensal microbiota. Moreover, we will employ animal models of E. coli and Salmonella colonization and infection to test our hypothesis that administration of our siderophore-?-lactam conjugates will more selectively target E. coli and Salmonella and be effective at lower doses than the parent ?-lactam antibiotics. Taken together, the results from these investigations will provide the foundation for the future development of siderophore-based tools to study and manipulate the microbiota, as well as therapeutic approaches to treat bacterial infections caused by Gram- negative pathogens that harness the iron acquisition systems employed by these deleterious organisms when colonizing the mammalian host.

Public Health Relevance

Gram-negative bacterial pathogens are among the leading causes of morbidity in the United States and cause diseases that include diarrhea, urinary tract infections, pneumonia, and sepsis. Because of the rise of antibiotic resistance, new antibacterial therapeutic strategies that have minimal perturbation on the commensal microbiota are needed. Gram-negative pathogens use siderophores to acquire the essential nutrient iron in the host, and siderophore-based antibiotics provide a means to target groups of bacterial pathogens based on the expression and utilization of siderophore receptors that will reduce the spread of antibiotic resistance, thereby addressing this important public health issue.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI126465-02
Application #
9292254
Study Section
Special Emphasis Panel (ZRG1-IDM-B (80)S)
Program Officer
Alexander, William A
Project Start
2016-06-10
Project End
2018-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
2
Fiscal Year
2017
Total Cost
$175,161
Indirect Cost
$27,676
Name
Massachusetts Institute of Technology
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02142
Neumann, Wilma; Sassone-Corsi, Martina; Raffatellu, Manuela et al. (2018) Esterase-Catalyzed Siderophore Hydrolysis Activates an Enterobactin-Ciprofloxacin Conjugate and Confers Targeted Antibacterial Activity. J Am Chem Soc 140:5193-5201
Neumann, Wilma; Nolan, Elizabeth M (2018) Evaluation of a reducible disulfide linker for siderophore-mediated delivery of antibiotics. J Biol Inorg Chem 23:1025-1036
Chung, Lawton K; Raffatellu, Manuela (2018) G.I. pros: Antimicrobial defense in the gastrointestinal tract. Semin Cell Dev Biol :
Zamora, Cristina Y; Madec, Amaƫl G E; Neumann, Wilma et al. (2018) Design, solid-phase synthesis and evaluation of enterobactin analogs for iron delivery into the human pathogen Campylobacter jejuni. Bioorg Med Chem 26:5314-5321
Neumann, Wilma; Gulati, Anmol; Nolan, Elizabeth M (2017) Metal homeostasis in infectious disease: recent advances in bacterial metallophores and the human metal-withholding response. Curr Opin Chem Biol 37:10-18
Neumann, Wilma; Hadley, Rose C; Nolan, Elizabeth M (2017) Transition metals at the host-pathogen interface: how Neisseria exploit human metalloproteins for acquiring iron and zinc. Essays Biochem 61:211-223
Johnstone, Timothy C; Nolan, Elizabeth M (2017) Determination of the Molecular Structures of Ferric Enterobactin and Ferric Enantioenterobactin Using Racemic Crystallography. J Am Chem Soc 139:15245-15250