Imaging sensitive and drug-resistant bacterial infection with [11C]-trimethoprim

作者：Iris K. Lee, Daniel A. Jacome, Joshua K. Cho, Vincent Tu, Anthony J. Young, Tiffany Dominguez, Justin D. Northrup, Jean M. Etersque, Hsiaoju Lee, Andrew Ruff, Ouniol Aklilu, Kyle Bittinger, Laurel Glaser, Daniel Dorgan, Denis Hadjiliadis, Rahul M. Kohli, Robert H. Mach, David A. Mankoff, Robert K. Doot, Mark A. Sellmyer · 发表于：Journal of Clinical Investigation · 年份：2022 · DOI：10.1172/jci156679 · 被引用次数：34 · 研究领域：Infective Endocarditis Diagnosis and Management、Infectious Diseases and Tuberculosis、Tuberculosis Research and Epidemiology

BACKGROUNDSeveral molecular imaging strategies can identify bacterial infections in humans. PET affords the potential for sensitive infection detection deep within the body. Among PET-based approaches, antibiotic-based radiotracers, which often target key bacterial-specific enzymes, have considerable promise. One question for antibiotic radiotracers is whether antimicrobial resistance (AMR) reduces specific accumulation within bacteria, diminishing the predictive value of the diagnostic test.METHODSUsing a PET radiotracer based on the antibiotic trimethoprim (TMP), [11C]-TMP, we performed in vitro uptake studies in susceptible and drug-resistant bacterial strains and whole-genome sequencing (WGS) in selected strains to identify TMP resistance mechanisms. Next, we queried the NCBI database of annotated bacterial genomes for WT and resistant dihydrofolate reductase (DHFR) genes. Finally, we initiated a first-in-human protocol of [11C]-TMP in patients infected with both TMP-sensitive and TMP-resistant organisms to demonstrate the clinical feasibility of the tool.RESULTSWe observed robust [11C]-TMP uptake in our panel of TMP-sensitive and -resistant bacteria, noting relatively variable and decreased uptake in a few strains of P. aeruginosa and E. coli. WGS showed that the vast majority of clinically relevant bacteria harbor a WT copy of DHFR, targetable by [11C]-TMP, and that despite the AMR, these strains should be "imageable." Clinical imaging of patients with [11C]-TMP demonst...