Imaging Sensitive and Drug-Resistant Bacterial Infection with [11C]-TMP: In Vitro and First-in-Human Evaluation

Recently, several molecular imaging strategies have developed to image bacterial infections in humans. Nuclear approaches, specifically positron emission tomography (PET), affords sensitive detection and the ability to non-invasively locate infections deep within the body. Two key radiotracer classes have arisen: metabolic approaches targeting bacterial specific biochemical transformations, and antibiotic-based approaches that have inherent selectivity for bacteria over mammalian cells. A critical question for clinical application of antibiotic radiotracers is whether resistance to the template antibiotic abrogates specific uptake, thus diminishing the predictive value of the diagnostic test. We recently developed small-molecule PET radiotracers based on the antibiotic trimethoprim (TMP), including [11C]-TMP, and have shown their selectivity for imaging bacteria in preclinical models. Here, we measure the in vitro uptake of [11C]-TMP in pathogenic susceptible and drug-resistant bacterial strains. Both resistant and susceptible bacteria showed similar in vitro uptake, which led us to perform whole genome sequencing of these isolates to identify the mechanisms of TMP resistance that permit retained radiotracer binding. By interrogating these isolate genomes and a broad panel of previously sequenced strains, we reveal mechanisms where uptake or binding of TMP radiotracers can potentially be maintained despite the annotation of genes conferring antimicrobial resistance. Finally, we present several examples of patients with both TMP-sensitive and drug-resistant infections in our first-in-human experience with [11C]-TMP. This work underscores the ability of an antibiotic radiotracer to image bacterial infection in patients, which may allow insights into human bacterial pathogenesis, infection diagnosis, and antimicrobial response monitoring.

Screening Ethanolic Extract of Aerva lanata for α-Amylase Inhibition and in vitro Uptake of Glucose in Adipose Tissue and Psoas Muscle of Male Sprague Dawley Rats

The study was intended to investigate anti-diabetic efficacy of Aerva lanata by determining its α-amylase inhibition activity and in vitro uptake of glucose in adipose tissue and psoas muscle isolated from male Sprague Dawley (SD) rats. Aerva lanata is reported to have many traditional and Ayurvedic uses. Male SD rats (n=3) of 150 g were sacrificed and 250 mg of respective tissues were isolated for the study. Aerva lanata ethanolic extract (ALE) (5-20 mg/mL) showed 13.30 to 54.08% α-amylase inhibition activity. Glucose uptake studies in in vitro conditions were carried out in both adipose tissue and psoas muscle in different sets - tissue alone, tissue along with (Aerva lanata extract: 50μg, 100μg, 150μg, insulin: 25 mU/L, insulin: 50 mU/L and Aerva lanata extract: 50μg + insulin: 25 mU/L, Aerva lanata extract: 100μg + insulin: 25 mU/L, Aerva lanata extract: 150μg + insulin: 25 mU/L, Aerva lanata extract: 50μg + insulin: 50 mU/L, Aerva lanata extract: 100μg + insulin: 50 mU/L, Aerva lanata extract: 150μg + insulin: 50 mU/L). The rate of glucose uptake by insulin action in these tissues was stabilized by ethanolic extract of Aerva lanata and this shows synergetic activity of insulin and Aerva lanata.