Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907-2027, USA.
Department of Chemistry, Purdue University, West Lafayette, IN 47907-2084, USA.
Biochim Biophys Acta Gen Subj. 2017 Apr;1861(4):848-859. doi: 10.1016/j.bbagen.2017.01.029. Epub 2017 Jan 27.
The worldwide emergence of antibiotic resistance represents a serious medical threat. The ability of these resistant pathogens to form biofilms that are highly tolerant to antibiotics further aggravates the situation and leads to recurring infections. Thus, new therapeutic approaches that adopt novel mechanisms of action are urgently needed. To address this significant problem, we conjugated the antibiotic kanamycin with a novel antimicrobial peptide (P14LRR) to develop a kanamycin peptide conjugate (P14KanS).
Antibacterial activities were evaluated in vitro and in vivo using a Caenorhabditis elegans model. Additionally, the mechanism of action, antibiofilm activity and anti-inflammatory effect of P14KanS were investigated.
P14KanS exhibited potent antimicrobial activity against ESKAPE pathogens. P14KanS demonstrated a ≥128-fold improvement in MIC relative to kanamycin against kanamycin-resistant strains. Mechanistic studies confirmed that P14KanS exerts its antibacterial effect by selectively disrupting the bacterial cell membrane. Unlike many antibiotics, P14KanS demonstrated rapid bactericidal activity against stationary phases of both Gram-positive and Gram-negative pathogens. Moreover, P14KanS was superior in disrupting adherent bacterial biofilms and in killing intracellular pathogens as compared to conventional antibiotics. Furthermore, P14KanS demonstrated potent anti-inflammatory activity via the suppression of LPS-induced proinflammatory cytokines. Finally, P14KanS protected C. elegans from lethal infections of both Gram-positive and Gram-negative pathogens.
The potent in vitro and in vivo activity of P14KanS warrants further investigation as a potential therapeutic agent for bacterial infections.
This study demonstrates that equipping kanamycin with an antimicrobial peptide is a promising method to tackle bacterial biofilms and address bacterial resistance to aminoglycosides.
抗生素耐药性的全球出现是一个严重的医学威胁。这些耐药病原体形成高度耐受抗生素的生物膜的能力进一步加剧了这种情况，并导致反复感染。因此，迫切需要采用新作用机制的新治疗方法。为了解决这个重大问题，我们将抗生素卡那霉素与一种新型抗菌肽（P14LRR）结合，开发了一种卡那霉素肽缀合物（P14KanS）。
使用秀丽隐杆线虫模型评估了体外和体内的抗菌活性。此外，还研究了 P14KanS 的作用机制、抗生物膜活性和抗炎作用。
P14KanS 对 ESKAPE 病原体表现出强大的抗菌活性。与卡那霉素相比，P14KanS 对卡那霉素耐药株的 MIC 提高了 128 倍以上。机制研究证实，P14KanS 通过选择性破坏细菌细胞膜发挥其抗菌作用。与许多抗生素不同，P14KanS 对革兰氏阳性和革兰氏阴性病原体的静止期均具有快速杀菌活性。此外，与传统抗生素相比，P14KanS 更能破坏附着的细菌生物膜并杀死细胞内病原体。此外，P14KanS 通过抑制 LPS 诱导的促炎细胞因子发挥强大的抗炎活性。最后，P14KanS 保护秀丽隐杆线虫免受革兰氏阳性和革兰氏阴性病原体的致命感染。
P14KanS 的强大体外和体内活性使其有潜力成为治疗细菌感染的潜在治疗剂，值得进一步研究。
这项研究表明，用抗菌肽装备卡那霉素是一种有前途的方法，可以解决细菌生物膜问题，并解决细菌对氨基糖苷类药物的耐药性。
