Design of a PEGylated Antimicrobial Prodrug with Species-Specific Activation.
Design of a PEGylated Antimicrobial Prodrug with Species-Specific Activation.
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DOI：
10.1021/acs.biomac.0c01695
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发表时间：
2021-02-08
影响因子：
6.2
通讯作者：
Alabi CA
中科院分区：
文献类型：
--
作者：
O'Leary MK;Chen SS;Westblade LF;Alabi CA
多药耐药（MDR）“超级细菌”的出现迫切需要开发新的抗菌药物来靶向这些生物体。寡聚硫醚酰胺（oligothiothietheramides，oligTEA）是一类独特的抗菌肽（AMP）模拟物，其中一种有前途的化合物BDT-4G显示出对MDR铜绿假单胞菌临床分离株的有效活性。尽管BDT-4G和其他AMP模拟物的效力得到广泛证实，但它们尚未在临床前获得广泛的成功，主要是由于它们的细胞毒性。在这项工作中，我们探索了一种前药策略，使BDT-4G失活，直到它暴露于靶细菌分泌的酶。前药由通过肽底物与BDT-4G缀合的聚乙二醇（PEG）组成。PEG通过掩蔽BDT-4G的阳离子电荷来抑制和降低BDT-4G的毒性，并且在由铜绿假单胞菌分泌的毒力因子LasA对短肽接头进行位点特异性切割后恢复抗微生物活性。这种方法同时在体外将细胞毒性降低超过一个数量级，并通过可切割接头的身份提供物种特异性。
The rise of multidrug-resistant (MDR) “superbugs” has created an urgent need to develop new classes of antimicrobial agents to target these organisms. Oligothioetheramides (oligoTEAs) are a unique class of antimicrobial peptide (AMP) mimetics, with one promising compound, BDT-4G displaying potent activity against MDR Pseudomonas aeruginosa clinical isolates. Despite widely demonstrated potency, BDT-4G and other AMP mimetics have yet to enjoy broad preclinical success against systemic infections, primarily due to their cytotoxicity. In this work, we explore a prodrug strategy to render BDT-4G inactive until it is exposed to an enzyme secreted by the targeted bacteria. The prodrug consists of polyethylene glycol (PEG) conjugated to BDT-4G by a peptide substrate. PEG serves to inactivate and reduce the toxicity of BDT-4G by masking its cationic charge and antimicrobial activity is recovered following site-specific cleavage of the short peptide linker by LasA, a virulence factor secreted by P. aeruginosa. This approach concurrently reduces cytotoxicity by greater than one order of magnitude in vitro and provides species specificity through the identity of the cleavable linker.
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