Sensing Living Bacteria in Vivo Using d-Alanine-Derived 11C Radiotracers.,ACS Central Science

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Sensing Living Bacteria in Vivo Using d-Alanine-Derived 11C Radiotracers.
ACS Central Science ( IF 12.7 ) Pub Date : 2020-02-04 , DOI: 10.1021/acscentsci.9b00743
Matthew F L Parker ₁ , Justin M Luu ₁ , Brailee Schulte ₁ , Tony L Huynh ₁ , Megan N Stewart ₁ , Renuka Sriram ₁ , Michelle A Yu ₂ , Salma Jivan ₁ , Peter J Turnbaugh ₃ , Robert R Flavell ₁ , Oren S Rosenberg ₂ , Michael A Ohliger _{1,

4} , David M Wilson ₁

Affiliation

Incorporation of d-amino acids into peptidoglycan is a unique metabolic feature of bacteria. Since d-amino acids are not metabolic substrates in most mammalian tissues, this difference can be exploited to detect living bacteria in vivo. Given the prevalence of d-alanine in peptidoglycan muropeptides, as well as its role in several antibiotic mechanisms, we targeted this amino acid for positron emission tomography (PET) radiotracer development. d-[3-11C]Alanine and the dipeptide d-[3-11C]alanyl-d-alanine were synthesized via asymmetric alkylation of glycine-derived Schiff-base precursors with [11C]methyl iodide in the presence of a cinchonidinium phase-transfer catalyst. In cell experiments, both tracers showed accumulation by a wide variety of both Gram-positive and Gram-negative pathogens including Staphylococcus aureus and Pseudomonas aeruginosa. In a mouse model of acute bacterial myositis, d-[3-11C]alanine was accumulated by living microorganisms but was not taken up in areas of sterile inflammation. When compared to existing clinical nuclear imaging tools, specifically 2-deoxy-2-[18F]fluoro-d-glucose and a gallium citrate radiotracer, d-alanine showed more bacteria-specific uptake. Decreased d-[3-11C]alanine uptake was also observed in antibiotic-sensitive microbes after antimicrobial therapy, when compared to that in resistant organisms. Finally, prominent uptake of d-[3-11C]alanine uptake was seen in rodent models of discitis-osteomyelitis and P. aeruginosa pneumonia. These data provide strong justification for clinical translation of d-[3-11C]alanine to address a number of important human infections.

中文翻译：

使用 d-丙氨酸衍生的 11C 放射性示踪剂感测体内活细菌。

将 d-氨基酸掺入肽聚糖中是细菌独特的代谢特征。由于 d-氨基酸不是大多数哺乳动物组织中的代谢底物，因此可以利用这种差异来检测体内活细菌。鉴于 d-丙氨酸在肽聚糖壁肽中的普遍存在及其在多种抗生素机制中的作用，我们针对这种氨基酸进行正电子发射断层扫描 (PET) 放射性示踪剂的开发。 d-[3-11C]丙氨酸和二肽 d-[3-11C]丙氨酰-d-丙氨酸是通过甘氨酸衍生的希夫碱前体与[11C]甲基碘在辛可尼鎓相存在下进行不对称烷基化合成的。转移催化剂。在细胞实验中，两种示踪剂都显示出多种革兰氏阳性和革兰氏阴性病原体的积累，包括金黄色葡萄球菌和铜绿假单胞菌。在急性细菌性肌炎的小鼠模型中，d-[3-11C]丙氨酸由活微生物积累，但没有被无菌炎症区域吸收。与现有的临床核成像工具（特别是 2-脱氧-2-[18F]氟-d-葡萄糖和柠檬酸镓放射性示踪剂）相比，d-丙氨酸显示出更多的细菌特异性摄取。与耐药微生物相比，抗生素敏感微生物在抗菌治疗后也观察到 d-[3-11C]丙氨酸摄取减少。最后，在椎间盘炎骨髓炎和铜绿假单胞菌肺炎的啮齿动物模型中观察到d-[3-11C]丙氨酸的显着摄取。这些数据为 d-[3-11C]丙氨酸的临床转化来解决许多重要的人类感染提供了强有力的理由。

更新日期：2020-02-26

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