The Antistaphylococcal Lysin, CF-301, Activates Key Host Factors in Human Blood To Potentiate Methicillin-Resistant Staphylococcus aureus Bacteriolysis
The Antistaphylococcal Lysin, CF-301, Activates Key Host Factors in Human Blood To Potentiate Methicillin-Resistant Staphylococcus aureus Bacteriolysis
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DOI：
10.1128/aac.02291-18
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发表时间：
2019-04-01
影响因子：
4.9
通讯作者：
Schuch, Raymond
中科院分区：
文献类型：
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作者：
Indiani, Chiara;Sauve, Karen;Schuch, Raymond
噬菌体衍生的溶酶是一种细胞壁水解酶，代表着一种潜在的新型抗菌治疗药物的开发，以解决迅速增长的抗菌素耐药性。CF-301是这一类中的先导化合物，正在作为一种辅助治疗进行临床开发，当与抗生素一起使用时，可能会提高金黄色葡萄球菌菌血症和感染性心内膜炎(IE)的临床治愈率。为了描述CF-301在临床相关环境中的活性，我们评估了它在人血中的体外活性与在常规测试介质(阳离子调节的Mueller-Hinton肉汤[caMHB])中的活性。在三种标准的微生物测试形式(例如，肉汤稀释法、棋盘协同法和时间杀伤法)中，CF-301在人血中显示出比caMHB更大的效力(32to=100倍)。我们证明了CF-301与两种关键的人血液因子，人血清溶菌酶(HuLYZ)和人血清白蛋白(HSA)，对典型的甲氧西林耐药金黄色葡萄球菌(MW2)有协同作用，这两种因子通常没有新生的抗葡萄球菌活性。在兔、马和狗(但不是大鼠或小鼠)的血液中也观察到了类似的体外增强CF-301活性的现象。两个在兔和大鼠中建立的MRSA IE模型被用来在体内验证这些发现，证明了标准护理抗MRSA抗生素在兔体内的溶素剂量比大鼠模型低100倍时具有类似的协同效应。CF-301的独特性能能够通过激活人类血液中的“潜在”宿主因子来增强杀菌活性，这可能对持续改善严重耐药葡萄球菌感染的临床结果具有重要的治疗意义。
Bacteriophage-derived lysins are cell-wall-hydrolytic enzymes that represent a potential new class of antibacterial therapeutics in development to address burgeoning antimicrobial resistance. CF-301, the lead compound in this class, is in clinical development as an adjunctive treatment to potentially improve clinical cure rates of Staphylococcus aureus bacteremia and infective endocarditis (IE) when used in addition to antibiotics. In order to profile the activity of CF-301 in a clinically relevant milieu, we assessed its in vitro activity in human blood versus in a conventional testing medium (cation-adjusted Mueller-Hinton broth [caMHB]). CF-301 exhibited substantially greater potency (32 to >= 100-fold) in human blood versus caMHB in three standard microbiologic testing formats (e.g., broth dilution MICs, checkerboard synergy, and time-kill assays). We demonstrated that CF-301 acted synergistically with two key human blood factors, human serum lysozyme (HuLYZ) and human serum albumin (HSA), which normally have no nascent antistaphylococcal activity, against a prototypic methicillin-resistant S. aureus (MRSA) strain (MW2). Similar in vitro enhancement of CF-301 activity was also observed in rabbit, horse, and dog (but not rat or mouse) blood. Two well-established MRSA IE models in rabbit and rat were used to validate these findings in vivo by demonstrating comparable synergistic efficacy with standard-of-care anti-MRSA antibiotics at >= 100-fold lower lysin doses in the rabbit than in the rat model. The unique properties of CF-301 that enable bactericidal potentiation of antimicrobial activity via activation of "latent" host factors in human blood may have important therapeutic implications for durable improvements in clinical outcomes of serious antibiotic-resistant staphylococcal infections.