Antimicrobial resistance has a major public health risk where drugs are no longer effective against microorganisms. Once powerful antimicrobial agents have now become virtually useless, and the situation is spreading rapidly over the globe. The objective of this proposal is to develop a new strategy for targeting multidrug-resistant bacteria, composed of therapeutics-encapsulated nanoparticles with maltoheptaose (G7) as the targeting agent. The key hypothesis is that G7 will greatly facilitate the uptake of nanoparticles by bacterial cells whereas the multivalent nanoparticles will deliver high local doses of therapeutics into bacterial cells to achieve significantly enhanced antibiotic potency. G7, a maltodextrin that is the largest carbon source for metabolic activity, will be used as the targetin agent as we have shown that it drastically increased the uptake of nanoparticles by bacterial cells whereas it had minimal impact on mammalian cells. In addition, we hypothesize that G7-tagged nanoparticles will improve considerably the efficacy of antibiotics in treating multidrug-resistant bacterial infection. During the two-year project period, we will synthesize and study the antimicrobial activities of antibiotics-encapsulated G7-liposomes and G7-micelles against multidrug-resistant Pseudomonas aeruginosa in vitro. We will also evaluate the in vivo efficacy of the new nanotherapeutics using a mice model. The completion of these studies will demonstrate that G7-based nanotherapeutics will improve appreciably the therapeutic efficacy of antibiotics and revert the antimicrobial resistance of P. aeruginosa. The proposal is innovative because it represents the first study to use a nutrient as the targeting strategy for drug delivery The project is significant because results from these studies can be readily applied to other systems, thus a universal platform can be envisioned for enhancing the delivery of a diverse class of therapeutic agents to treat multidrug-resistant bacterial infections.

Public Health Relevance

Drug-resistance has become a major public health risk causing drastic increases in healthcare cost as well as mortality and morbidity. This proposal focuses on developing a new platform for treating drug-resistant infections. The strategy uses a bacterial nutrient, maltoheptaose, as the 'bait' to facilitate the entry of antibiotic-encapsulated nanoparticles into bacterial cells. This 'sweet Trojan horse' will greatly enhance the therapeutic efficacy of antibiotics, making them effective in treating drug-resistant bacterial infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI109896-02
Application #
8917852
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Xu, Zuoyu
Project Start
2014-09-01
Project End
2017-08-31
Budget Start
2015-09-01
Budget End
2017-08-31
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Massachusetts Lowell
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
956072490
City
Lowell
State
MA
Country
United States
Zip Code
Sundhoro, Madanodaya; Jeon, Seaho; Park, Jaehyeung et al. (2017) Perfluoroaryl Azide Staudinger Reaction: A Fast and Bioorthogonal Reaction. Angew Chem Int Ed Engl 56:12117-12121
Xie, Sheng; Manuguri, Sesha; Proietti, Giampiero et al. (2017) Design and synthesis of theranostic antibiotic nanodrugs that display enhanced antibacterial activity and luminescence. Proc Natl Acad Sci U S A 114:8464-8469
Hao, Nanjing; Chen, Xuan; Jayawardana, Kalana W et al. (2016) Shape control of mesoporous silica nanomaterials templated with dual cationic surfactants and their antibacterial activities. Biomater Sci 4:87-91
Hao, Nanjing; Neranon, Kitjanit; Ramström, Olof et al. (2016) Glyconanomaterials for biosensing applications. Biosens Bioelectron 76:113-30
Chen, Xuan; Wu, Bin; Jayawardana, Kalana W et al. (2016) Magnetic Multivalent Trehalose Glycopolymer Nanoparticles for the Detection of Mycobacteria. Adv Healthc Mater 5:2007-12
Jayawardana, Kalana W; Wijesundera, Samurdhi A; Yan, Mingdi (2015) Aggregation-based detection of M. smegmatis using D-arabinose-functionalized fluorescent silica nanoparticles. Chem Commun (Camb) 51:15964-6
Jayawardana, Kalana W; Jayawardena, H Surangi N; Wijesundera, Samurdhi A et al. (2015) Selective targeting of Mycobacterium smegmatis with trehalose-functionalized nanoparticles. Chem Commun (Camb) 51:12028-31
Hao, Nanjing; Jayawardana, Kalana W; Chen, Xuan et al. (2015) One-step synthesis of amine-functionalized hollow mesoporous silica nanoparticles as efficient antibacterial and anticancer materials. ACS Appl Mater Interfaces 7:1040-5
Ramström, Olof; Yan, Mingdi (2015) Glyconanomaterials for Combating Bacterial Infections. Chemistry 21:16310-7
Hao, Nanjing; Chen, Xuan; Jeon, Seaho et al. (2015) Carbohydrate-Conjugated Hollow Oblate Mesoporous Silica Nanoparticles as Nanoantibiotics to Target Mycobacteria. Adv Healthc Mater 4:2797-801