Hunting for Bugs

Bacteria are getting smarter. They’re hiding in new places in patients and finding ways to avoid medicines that would’ve killed them in the past. Scientists at BioMed Valley Discoveries are developing methods to find bacteria so they can be treated quickly before they cause life-threatening infections.

Studying Bacteria
The widespread use of modern antibiotics has produced new strains of bacteria that can resist previous treatments. In addition, increases in the use of prosthetic devices—joints especially—have given microbes new ways to get into the body and environments in which to grow. But decades of microbiological research have uncovered molecular mechanisms specific to bacteria—mechanisms that can be used to both find where bacteria are hiding and get rid of them.

Researchers have carefully studied the species-specific differences of certain enzymes. For example, nearly every cell, whether human, fruit fly, or bacterial, uses the enzyme thymidine kinase to help construct its DNA from basic chemical building blocks called nucleosides. Bacterial and even viral thymidine kinase differs in significant ways from the human form of this enzyme. Research has shown that these non-human thymidine kinases are more active on certain types of chemicals, including a nucleoside called FIAU (fialuridine.) This molecule has been used in the past to treat viral infections, including hepatitis B.

Imaging Diseases
BioMed Valley Discoveries’ scientists are exploiting this difference in enzymatic activity to identify small bacterial infections in patients with prosthetic joints before they become full-blown. It’s an increasingly urgent problem: musculoskeletal system infections are some of the most challenging to discover. Right now, doctors have a hard time diagnosing them because the infections often show non-specific symptoms in patients, such as diffuse pain that may be due to any number of unrelated causes like arthritis or other injury.

This problem can be successfully overcome by modern medical imagining technologies. Positron emission tomography or PET scans, which are widely used to diagnose tumors, metabolic disorders, and brain diseases, are one effective option. The technology relies on the use of ‘smart’ small molecule probes that target specific cells or cellular activities. These molecules are tagged with a radioactive label for easy detection.

In oncology, PET images help doctors determine the severity of cancer.
A patient with lung tumors, for example, would be given a solution containing a radiolabeled version of the sugar glucose. They would then be placed in a PET scanner, which is similar to an MRI machine, and radiologists could see the spread of cancerous cells in the patient because these cells rapidly absorb and use glucose. Studies in Europe have demonstrated that this technique can be used to identify brain tumors in human patients undergoing gene therapy. PET scanning is more sensitive than conventional medical imaging technologies such as X-rays, MRIs, and ultrasounds because it can pinpoint the areas in which radiolabeled molecules accumulate.

Prosthetics pose a particular problem for these imaging techniques, however. The metal and dense plastics in the joints can interfere with detection, cause anomalies, or obscure results. A misdiagnosis for these patients has crucial consequences: without appropriate treatment, the prosthetic may fail and may have to be replaced or removed completely. Approximately 15% of suspected joint infections can never be confirmed as true infections, and these patients often have to undergo replacement surgeries for otherwise treatable infections.

Our Goal: To Identify Infections
BioMed Valley Discoveries’ clinical study of bacterial infections makes use of a radiolabeled analog of FIAU (rFIAU), which is the molecule efficiently utilized by bacterial and viral thymidine kinase enzymes. When bacteria take up FIAU and process it with their thymidine kinase enzymes, the nucleoside becomes trapped. The bugs can then be detected with high resolution using PET imaging, as has been done for cancer patients using radiolabeled glucose. Experiments with rFIAU in mice have proven as much: infected muscle in these animals gave a much greater PET imaging signal than did non-infected tissue.

In our ongoing experiment, we recruit patients with suspected prosthetic joint infections of the knee or hip and administer rFIAU intravenously. We then image the patients with PET scans to track the infection. We aim to determine safe and tolerable doses of the nucleoside that can still sensitively detect bacterial infections. In addition, our study will help find the optimal imaging time and give us an understanding of the nature of the site of infection. In this way, BioMed Valley Discoveries’ research will give doctors a more sensitive tool to find—and eventually hunt—bacteria no matter where they’re hiding.