Department of Chemistry, University of Manitoba, Winnipeg, Manitoba, Canada.
Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.
Antimicrob Agents Chemother. 2018 Mar 27;62(4). doi: 10.1128/AAC.02374-17. Print 2018 Apr.
A series of 16 short proline-rich lipopeptides (SPRLPs) were constructed to mimic longer naturally existing proline-rich antimicrobial peptides. Antibacterial assessment revealed that lipopeptides containing hexadecanoic acid (C) possess optimal antibacterial activity relative to others with shorter lipid components. SPRLPs were further evaluated for their potential to serve as adjuvants in combination with existing antibiotics to enhance antibacterial activity against drug-resistant Out of 16 prepared SPRLPs, C-PRP was found to significantly potentiate the antibiotics minocycline and rifampin against multidrug- and extensively drug-resistant (MDR/XDR) clinical isolates. This nonhemolytic C-PRP is comprised of the heptapeptide sequence PRPRPRP-NH acylated to dodecanoic acid (C) at the N terminus. The adjuvant potency of C-PRP was apparent by its ability to reduce the MIC of minocycline and rifampin below their interpretative susceptibility breakpoints against MDR/XDR An attempt to optimize C-PRP through peptidomimetic modification was performed by replacing all l- to d-amino acids. C-PRP demonstrated that it was amenable to optimization, since synergism with minocycline and rifampin were retained. Moreover, C-PRP displayed no cytotoxicity against human liver carcinoma HepG2 and human embryonic kidney HEK-293 cell lines. Thus, the SPRLP C-PRP is a lead adjuvant candidate that warrants further optimization. The discovery of agents that are able to resuscitate the activity of existing antibiotics against drug-resistant Gram-negative pathogens, especially , is of great clinical interest.
构建了一系列 16 个短的脯氨酸丰富的脂肽（SPRLP），以模拟更长的天然存在的富含脯氨酸的抗菌肽。抗菌评估显示，含有十六烷酸（C）的脂肽相对于其他具有较短脂质成分的脂肽具有最佳的抗菌活性。进一步评估了 SPRLPs 作为与现有抗生素联合使用的佐剂的潜力，以增强对抗耐药性的抗菌活性。在制备的 16 个 SPRLPs 中，C-PRP 被发现可显著增强抗生素米诺环素和利福平对多药和广泛耐药（MDR/XDR）临床分离株的抗菌活性。这种非溶血的 C-PRP 由七肽序列 PRPRPRP-NH 酰化到十二烷酸（C）的 N 末端组成。C-PRP 的佐剂效力通过其降低米诺环素和利福平的 MIC 至低于其对 MDR/XDR 的解释性敏感性折点来显现。通过用 d-氨基酸替代所有 l-氨基酸来尝试优化 C-PRP。C-PRP 证明它是可优化的，因为它与米诺环素和利福平的协同作用得以保留。此外，C-PRP 对人肝癌 HepG2 和人胚肾 HEK-293 细胞系没有细胞毒性。因此，SPRLP C-PRP 是一个有前途的佐剂候选物，值得进一步优化。发现能够恢复现有抗生素对耐药革兰氏阴性病原体（尤其是 ）活性的药物具有重要的临床意义。
