He Peng, Li Xin, Guo Xiaohan, Bian Xingchen, Wang Rui, Wang Yue, Huang Sijing, Qi Mengya, Liu Yuanxia, Feng Meiqing
Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, People's Republic of China.
Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, People's Republic of China.
Infect Drug Resist. 2023 Feb 18;16:1019-1028. doi: 10.2147/IDR.S399150. eCollection 2023.
LYSC98 is a novel vancomycin derivative used for gram-positive bacterial infections. Here we compared the antibacterial activity of LYSC98 with vancomycin and linezolid in vitro and in vivo. Besides, we also reported the pharmacokinetic/pharmacodynamic (PK/PD) index and efficacy-target values of LYSC98.
The MIC values of LYSC98 were identified through broth microdilution method. A mice sepsis model was established to investigate the protective effect of LYSC98 in vivo. Single-dose pharmacokinetics of LYSC98 was studied in thigh-infected mice and liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was used to determine LYSC98 concentration in plasma. Dose fractionation studies were performed to evaluate different PK/PD indices. Two methicillin-resistant (MRSA) clinical strains were used in the dose ranging studies to determine the efficacy-target values.
LYSC98 showed a universal antibacterial effect in with a MIC range of 2-4 µg/mL. In vivo, LYSC98 demonstrated distinctive mortality protection in mice sepsis model with an ED value of 0.41-1.86 mg/kg. The pharmacokinetics results displayed maximum plasma concentration (C) 11,466.67-48,866.67 ng/mL, area under the concentration-time curve from 0 to 24 h (AUC) 14,788.42-91,885.93 ng/mL·h, and elimination half-life (T) 1.70-2.64 h, respectively. C/MIC ( 0.8941) was proved to be the most suitable PK/PD index for LYSC98 to predict its antibacterial efficacy. The magnitude of LYSC98 C/MIC associated with net stasis, 1, 2, 3 and 4 - log kill were 5.78, 8.17, 11.14, 15.85 and 30.58, respectively.
Our study demonstrates that LYSC98 is more effective than vancomycin either in killing vancomycin-resistant (VRSA) in vitro or treating infections in vivo, making it a novel and promising antibiotic. The PK/PD analysis will also contribute to the LYSC98 Phase I dose design.
LYSC98是一种用于革兰氏阳性菌感染的新型万古霉素衍生物。在此，我们比较了LYSC98与万古霉素和利奈唑胺在体外和体内的抗菌活性。此外，我们还报告了LYSC98的药代动力学/药效学（PK/PD）指标和疗效靶值。
采用肉汤微量稀释法确定LYSC98的最低抑菌浓度（MIC）值。建立小鼠脓毒症模型以研究LYSC98在体内的保护作用。在大腿感染小鼠中研究LYSC98的单剂量药代动力学，并采用液相色谱-串联质谱（LC-MS/MS）法测定血浆中LYSC98的浓度。进行剂量分割研究以评估不同的PK/PD指标。在剂量范围研究中使用两株耐甲氧西林金黄色葡萄球菌（MRSA）临床菌株来确定疗效靶值。
LYSC98显示出广泛的抗菌作用，MIC范围为2 - 4μg/mL。在体内，LYSC98在小鼠脓毒症模型中表现出显著的死亡率保护作用，ED值为0.41 - 1.86mg/kg。药代动力学结果显示最大血浆浓度（Cmax）为11,466.67 - 48,866.67ng/mL，0至24小时浓度-时间曲线下面积（AUC0 - 24h）为14,788.42 - 91,885.93ng/mL·h，消除半衰期（t1/2）分别为1.70 - 2.64小时。Cmax/MIC（>0.8941）被证明是预测LYSC98抗菌疗效最合适的PK/PD指标。与净停滞、1、2、3和4 - log杀灭相关的LYSC98 Cmax/MIC值分别为5.78、8.17、11.14、15.85和30.58。
我们的研究表明，LYSC98在体外杀灭耐万古霉素金黄色葡萄球菌（VRSA）或体内治疗感染方面比万古霉素更有效，使其成为一种新型且有前景的抗生素。PK/PD分析也将有助于LYSC98的I期剂量设计。
