Staphylococcus aureus and Pseudomonas aeruginosa are the leading causes of hospital-acquired infections and contribute significantly to morbidity and mortality [3, 4]. Standard treatment of infection entails repetitive high-dose administrations of antibiotics, but the treatment is often rendered ineffective due to poor delivery to sites of infection and drug resistance mechanisms preventing antibiotic access to intracellular drug targets (e.g. the drug-impermeable cell wall in gram-negative P. aeruginosa) [5, 6]. Skin infections that have invaded down to the muscles and fibers are also difficult-to-reach by free-antibiotic formulations and require surgical treatment [7]. The obstacles we tackle in this proposal are: (1) loss of antibiotics to non-infected tissues; (2) rapid clearance of small molecule antibiotics by renal and gastrointestinal clearance; (3) poor penetration of drugs past the bacterial cell wall. We hypothesize that loading antibiotics into longer-circulating nanovehicles that will home to sites of infection and subsequently facilitate drug uptake into cells/bacteria of interest can overcome the abovementioned challenges. Here, we propose to develop such nanoplatforms through three major aims.
In Aim 1, we will use in vivo phage display to identify peptides that will home to the bacteria of interest and/or infected tissue. We will focus specifically on S. aureus and P. aeruginosa infections in models of deep skin (invasion in muscles and fibers) infection and pneumonia in mice. In the event that direct bacteria- targeting proves to be difficult, we will also look at peptides that bind selectively to infected tissues and host cells surrounding the bacterial colonies, as well as macrophage-targeting peptides. As these peptides are to be conjugated to nanoparticle surfaces, we will then investigate the binding properties of the peptides in singular and multivalent forms.
In Aim 2, we will engineer two nanoplatforms: (1) peptide-based agents that can selectively penetrate the bacterial membrane (i.e. peptide permeation agents) to which small molecule drugs will be tethered for increased uptake and (2) porous silicon nanoparticles (pSiNP) to load drugs that have poor delivery to sites of infection due to unfavorable physicochemical properties (hydrophobic, highly ionic, etc). These nanoplatforms will be targeted to sites of infection using peptides we have previously discovered or additional peptides to be identified in Aim 1. Model drugs with poor in vivo antibacterial activity will be loaded and optimal platforms selected based on drug loading, release kinetics, and cellular uptake for in vivo pharmacokinetics. In addition to individual pSi- and peptide-based nanoplatforms, we will develop a combined system in which bacteria-penetrating drug conjugates are loaded into targeted pSi nanoparticles with the goal of enhanced efficacy. Finally, Aim 3 will focus on the therapeutic performance of lead nanoplatform candidates in vivo. The goal of this aim is to demonstrate the biosafety and therapeutic efficacy (i.e. bacterial burden clearance, tissue recovery, improved survival) of the pSiNP and bacteria-penetrating nanosystems. This project will yield tools to actively target infected tissues as well as a strong set of nanoplatforms that can address many of the current barriers to in vivo antibacterial drug activity.

Public Health Relevance

We will identify infection-homing peptides and apply them to two nanoplatforms that carry small molecules: peptide-based and porous silicon-based. We will optimize and select individual and combined nanoplatforms to treat in vivo Staphylococcus aureus and Pseudomonas aeruginosa infections with lab and clinical strains of bacteria.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI132413-04
Application #
9953945
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Ernst, Nancy L
Project Start
2017-07-01
Project End
2022-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California, San Diego
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Kang, Jinyoung; Kim, Dokyoung; Wang, Junxin et al. (2018) Enhanced Performance of a Molecular Photoacoustic Imaging Agent by Encapsulation in Mesoporous Silicon Nanoparticles. Adv Mater 30:e1800512
Kumeria, Tushar; Wang, Joanna; Chan, Nicole et al. (2018) Visual Sensor for Sterilization of Polymer Fixtures Using Embedded Mesoporous Silicon Photonic Crystals. ACS Sens 3:143-150
Kim, Byungji; Pang, Hong-Bo; Kang, Jinyoung et al. (2018) Immunogene therapy with fusogenic nanoparticles modulates macrophage response to Staphylococcus aureus. Nat Commun 9:1969
Hussain, Sazid; Joo, Jinmyoung; Kang, Jinyoung et al. (2018) Antibiotic-loaded nanoparticles targeted to the site of infection enhance antibacterial efficacy. Nat Biomed Eng 2:95-103
Jin, Yusung; Kim, Dokyoung; Roh, Hajung et al. (2018) Tracking the Fate of Porous Silicon Nanoparticles Delivering a Peptide Payload by Intrinsic Photoluminescence Lifetime. Adv Mater 30:e1802878