Colombatti Olivieri Maria A, Cassmann Eric D, Jackson Michael A, Price Neil P J, Bannantine John P
USDA-Agricultural Research Service-National Animal Disease Center, Ames, Iowa, United States of America.
Oak Ridge Institute for Science and Education (ORISE), ARS Participation Program, Oak Ridge, Tennessee, United States of America.
PLoS One. 2025 Jul 23;20(7):e0327932. doi: 10.1371/journal.pone.0327932. eCollection 2025.
We have investigated the pharmacokinetics of TunR2, a modified tunicamycin-type antibiotic, in mice and cattle. TunR2 has previously been shown to be effective in a mycobacterial disease model using zebrafish, with a minimal activation of the eukaryotic unfolded protein response (upr) and a reduction in the in vivo mycobacterial burden. In this study, we presented statistically relevant pharmacokinetics of native tunicamycin (Tun) and two less toxic modified analogs, TunR2 and TunR1, using a well-defined clonal C57BL/6 mouse (both male and female). Blood samples were collected at multiple time points, and plasma concentrations were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Pharmacokinetic parameters were calculated using a two-compartment analysis. Our findings indicate that Tun and TunR1 tend to distribute in tissue compared to TunR2, which has a longer half-life than Tun. This translates into longer TunR2 activity time, potentially allowing for less frequent dosing than Tun or TunR1. We subsequently administered the modified TunR2 to Holstein cattle using a three-bolus intravenous regimen. We monitored blood, milk, urine, and feces over 90 days. In dairy cattle, the pharmacokinetics of TunR2 appear to be cumulative, and clear after 10 days. These findings provide critical new insights into the pharmacokinetics of TunR2. We concluded that TunR2 has considerable potential for treating bacterial infections, particularly as an antimicrobial adjuvant with well-established β-lactam antibiotics. Further studies are required to study safety and optimize dosing regimens for effective therapeutic use, as well as in combination with other antibiotics, such as β-lactams.
我们研究了一种改良的衣霉素型抗生素TunR2在小鼠和牛体内的药代动力学。此前已证明TunR2在使用斑马鱼的分枝杆菌病模型中有效，对真核未折叠蛋白反应（upr）的激活最小，并能降低体内分枝杆菌负荷。在本研究中，我们使用明确的克隆C57BL/6小鼠（雄性和雌性），给出了天然衣霉素（Tun）以及两种毒性较小的改良类似物TunR2和TunR1具有统计学意义的药代动力学。在多个时间点采集血样，并使用液相色谱 - 串联质谱法（LC-MS/MS）对血浆浓度进行定量。使用二室分析计算药代动力学参数。我们的研究结果表明，与TunR2相比，Tun和TunR1倾向于在组织中分布，TunR2的半衰期比Tun长。这意味着TunR2的活性时间更长，可能允许给药频率低于Tun或TunR1。随后，我们采用三次静脉推注方案给荷斯坦奶牛施用改良后的TunR2。我们在90天内监测血液、牛奶、尿液和粪便。在奶牛中，TunR2的药代动力学似乎具有累积性，10天后清除。这些发现为TunR2的药代动力学提供了重要的新见解。我们得出结论，TunR2在治疗细菌感染方面具有相当大的潜力，特别是作为一种与成熟的β-内酰胺抗生素联用的抗菌佐剂。需要进一步研究其安全性并优化给药方案以实现有效的治疗应用，以及与其他抗生素（如β-内酰胺类）联合使用。
