This proposal addresses a major challenge that radiologists and other physicians encounter frequently, namely distinguishing active infection from other processes in the human body. Existing clinical techniques generally target the host immune response, for example 111In SPECT white blood cell scanning or 18F-FDG PET. Although these modalities can sometimes be useful, they lack the specificity required to distinguish living bacteria from sterile inflammation, cancer, and other highly metabolic tissues. The central hypothesis of this proposal is that imaging bacteria-specific metabolic pathways will afford a highly accurate method to detect bacterial infections in vivo. We have identified 11C-PABA as a radiotracer with (1) a simple, high- yield radio-synthesis (2) good in vivo stability (3) appropriate mimicry of the endogenous substrate (4) rapid (minutes) rate of incorporation into both Gram-negative and Gram-positive bacteria, including clinical strains and multi-drug resistant organisms and (5) low uptake in background tissues. We propose a multi-PI and interdisciplinary collaboration across two institutions (University of California, San Francisco ? UCSF and Johns Hopkins) to validate 11C-PABA PET as a bacteria-specific imaging tool for spinal infections and study it for the first time in human patients. We will investigate the sensitivity of 11C-PABA for several relevant microorganisms, and compare its specificity to that of 18F-FDG and 68Ga-citrate in mouse models (Specific Aim 1). We will then study 11C-PABA in compelling preclinical infection models, assessing in vivo Gram-staining via a dual-tracer approach, rapid imaging readouts for antibiotic efficacy and evaluating tracer performance in rat models of vertebral osteomyelitis-discitis (Specific Aim 2).
In Specific Aim 3, we will translate 11C-PABA under the Radioactive Drug Research Committee (RDRC) program and study its performance in patients suffering from spinal infection. Any imaging method that could confirm presence of infection as well as guide antibiotic therapy would be profoundly helpful in clinical practice, sparing patients exposure to inappropriate broad spectrum antibiotics, invasive tissue sampling and reducing the risks of antibiotic resistance. Finally, while the focus of this application is on spinal infections, a clinically translatable bacteria-specific PET tracer would revolutionize the workup and management of a large variety of clinically relevant bacterial infections.

Public Health Relevance

This proposal describes a new technology to image infection in the human body, exploiting a metabolic pathway used only by bacteria. Specifically, bacteria are able to synthesize folic acid (Vitamin B9) whereas humans must ingest it. This difference will be used to develop a positron emission tomography (PET) technique to image spinal infection in patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB025985-03
Application #
9859397
Study Section
Clinical Molecular Imaging and Probe Development (CMIP)
Program Officer
Atanasijevic, Tatjana
Project Start
2018-05-01
Project End
2022-01-31
Budget Start
2020-02-01
Budget End
2021-01-31
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
Dumont, Rebecca A; Keen, Nayela N; Bloomer, Courtnay W et al. (2018) Clinical Utility of Diffusion-Weighted Imaging in Spinal Infections. Clin Neuroradiol :
Talbott, Jason F; Shah, Vinil N; Uzelac, Alina et al. (2018) Imaging-Based Approach to Extradural Infections of the Spine. Semin Ultrasound CT MR 39:570-586
Mutch, Christopher A; Ordonez, Alvaro A; Qin, Hecong et al. (2018) [11C]Para-Aminobenzoic Acid: A Positron Emission Tomography Tracer Targeting Bacteria-Specific Metabolism. ACS Infect Dis 4:1067-1072
Sriram, Renuka; Sun, Jinny; Villanueva-Meyer, Javier et al. (2018) Detection of Bacteria-Specific Metabolism Using Hyperpolarized [2-13C]Pyruvate. ACS Infect Dis 4:797-805
Neumann, Kiel D; Villanueva-Meyer, Javier E; Mutch, Christopher A et al. (2017) Imaging Active Infection in vivo Using D-Amino Acid Derived PET Radiotracers. Sci Rep 7:7903