奥马环素对疟原虫的体外活性和体内疗效。
In vitro activity and in vivo efficacy of omadacycline against Plasmodium species.
作者信息
Madejczyk Michael S, Leed Susan E, Kudyba Karl, Roth Alison, Martin Monica L, Lee Patricia, Anastasiou Diane, Pierce Jessica V, Serio Alisa W, Caridha Diana
机构信息
Experimental Therapeutics Branch, Center of Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, MD, 20910, USA.
ORISE Fellow, Walter Reed Army Institute of Research, Silver Spring, MD, 20910, USA.
出版信息
Malar J. 2025 Jun 19;24(1):194. doi: 10.1186/s12936-025-05448-w.
BACKGROUND
Doxycycline is currently the only tetracycline-class antibiotic recommended for malaria prophylaxis. Omadacycline, a semisynthetic aminomethylcycline approved for treatment of adults with community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections, has a well-established safety profile. This study evaluated the in vitro activity of omadacycline against Plasmodium falciparum and Plasmodium cynomolgi and its in vivo efficacy against Plasmodium berghei in experimental malaria models to assess its potential as an antimalarial drug.
METHODS
Fluorescence-based assays were used to assess the in vitro blood and liver stage activity of omadacycline and doxycycline against P. falciparum and P. cynomolgi laboratory clones. In vivo liver and early-stage blood stage efficacy were evaluated in a murine model of P. berghei infection, utilizing in vivo imaging of luciferase-expressing P. berghei (ANKA strain) sporozoites in female albino C57Bl/6 mice. Parasitaemia was monitored by flow cytometry for up to 30 days post-infection.
RESULTS
Omadacycline demonstrated comparable in vitro activity to doxycycline against both drug-sensitive and drug-resistant P. falciparum clones, while doxycycline showed reduced activity against two drug-resistant clones. Notably, omadacycline exhibited superior anti-schizont activity in the P. cynomolgi liver stage assay. In the P. berghei murine model, omadacycline was efficacious in both liver and early blood stages compared to the untreated control group, and demonstrated improved survival compared to doxycycline.
CONCLUSIONS
Omadacycline demonstrated enhanced antimalarial efficacy over doxycycline in vitro in liver stage activity and in overcoming resistance in the blood stage, and in survival in an in vivo model of P. berghei infection. These findings support further investigation of omadacycline as a potential candidate for malaria prophylaxis and treatment.
背景
多西环素是目前唯一推荐用于疟疾预防的四环素类抗生素。奥马环素是一种半合成氨基甲基环素，已被批准用于治疗成人社区获得性细菌性肺炎和急性细菌性皮肤及皮肤结构感染，其安全性已得到充分确立。本研究评估了奥马环素对恶性疟原虫和食蟹猴疟原虫的体外活性及其在实验性疟疾模型中对伯氏疟原虫的体内疗效，以评估其作为抗疟药物的潜力。
方法
采用基于荧光的检测方法评估奥马环素和多西环素对恶性疟原虫和食蟹猴疟原虫实验室克隆株的体外血液期和肝期活性。利用表达荧光素酶的伯氏疟原虫（ANKA株）子孢子在雌性白化C57Bl/6小鼠体内的成像，在伯氏疟原虫感染的小鼠模型中评估体内肝期和早期血液期疗效。通过流式细胞术监测感染后长达30天的寄生虫血症。
结果
奥马环素对药物敏感和耐药的恶性疟原虫克隆株的体外活性与多西环素相当，而多西环素对两个耐药克隆株的活性降低。值得注意的是，奥马环素在食蟹猴疟原虫肝期检测中表现出优异的抗裂殖体活性。在伯氏疟原虫小鼠模型中，与未治疗的对照组相比，奥马环素在肝期和早期血液期均有效，并且与多西环素相比生存率有所提高。
结论
奥马环素在体外肝期活性、克服血液期耐药性以及在伯氏疟原虫感染的体内模型中的生存率方面显示出比多西环素更强的抗疟疗效。这些发现支持进一步研究奥马环素作为疟疾预防和治疗的潜在候选药物。
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