Efficacious Analogs of the Lantibiotic Mutacin 1140 against a Systemic Methicillin-Resistant Staphylococcus aureus Infection
Efficacious Analogs of the Lantibiotic Mutacin 1140 against a Systemic Methicillin-Resistant Staphylococcus aureus Infection
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DOI：
10.1128/aac.01626-18
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发表时间：
2018-12-01
影响因子：
4.9
通讯作者：
Smith, Leif
中科院分区：
文献类型：
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作者：
Geng, Mengxin;Ravichandran, Akshaya;Smith, Leif
突变蛋白1140是AI型羊毛硫抗生素的表皮蛋白家族的成员，具有广谱抗革兰氏阳性菌的活性。它通过与脂质II结合来阻断细胞壁合成。虽然它具有快速杀菌作用和对革兰氏阳性病原体的有效活性，但其快速清除和体内半衰期短限制了其在临床上的发展。在这项研究中，我们评估了带电和脱水残基对变链蛋白1140药代动力学的影响。脱水残基被确定为有助于突变蛋白1140的稳定性，而丙氨酸取代赖氨酸或精氨酸残基改善了抗生素的药理学性质。类似物K2 A和R13 A具有显著较低的清除率，导致随着时间的推移血浆浓度较高。它们对几种病原菌的生物活性也有所提高。在小鼠全身性耐甲氧西林金黄色葡萄球菌（MRSA）感染模型中，10 mg/kg单次静脉推注K2 A和R13 A类似物（1：1比例）可保护100%的感染小鼠，而2.5 mg/kg剂量可导致50%的存活率。与溶剂对照组相比，10 mg/kg给药组肝脏和肾脏中的细菌负荷显著降低。该研究为未来开发用于治疗全身性革兰氏阳性菌感染的抗生素提供了先导化合物。
Mutacin 1140, a member of the epidermin family of type AI lantibiotics, has a broad spectrum of activity against Gram-positive bacteria. It blocks cell wall synthesis by binding to lipid II. Although it has rapid bactericidal effects and potent activity against Gram-positive pathogens, its rapid clearance and short half-life in vivo limit its development in the clinic. In this study, we evaluated the effect of charged and dehydrated residues on the pharmacokinetics of mutacin 1140. The dehydrated residues were determined to contribute to the stability of mutacin 1140, while alanine substitutions for the lysine or arginine residues improved the pharmacological properties of the antibiotic. Analogs K2A and R13A had significantly lower clearances, leading to higher plasma concentrations over time. They also had improved bioactivities against several pathogenic bacteria. In a murine systemic methicillin-resistant Staphylococcus aureus (MRSA) infection model, a 10-mg/kg single intravenous bolus injection of the K2A and R13A analogs (1:1 ratio) protected 100% of the infected mice, while a 2.5-mg/kg dose resulted in 50% survival. The 10-mg/kg treatment group had a significant reduction in bacteria load in the livers and kidneys compared to that in the vehicle control group. The study provides lead compounds for the future development of antibiotics used to treat systemic Grampositive infections.