The rapid emergence and dissemination of multidrug-resistant (MDR) bacterial pathogens pose a serious threat to global healthcare. One particular concern is the carbapenem-resistant Enterobacteriaceae (CRE), a group of Gram-negative bacteria that have evolved resistance to all or nearly all available antibiotics. Coupled with the fact of barren antibiotic development pipeline nowadays, a critical approach is to revitalize existing antibiotics using antibiotic adjuvants. We found a short linear antibacterial peptide (SLAP)-S25 carrying four non-natural amino acids of 2,4-diaminobutanoic acid (Dab), which solely showed weak antibacterial activity but boosted the efficacy of antibiotics covering all major classes, including cefepime, colistin, ofloxacin, rifampicin, tetracycline and vancomycin, against MDR Gram-negative pathogens. Mechanistic studies showed that SLAP-S25 triggers membrane damage by binding to both lipopolysaccharide (LPS) in the outer membrane and phosphatidylglycerol (PG) in bacterial cytoplasmic membrane, to potentiate antibiotic efficacy through collaborative strategies. Lastly, SLAP-S25 effectively enhanced the activity of colistin against MDR Escherichia coli-associated infections in three animal models. Our findings provide a potential therapeutic option using existing antibiotics in combination with broad-spectrum antibiotic adjuvants, to address the prevalent infections caused by MDR Gram-negative pathogens worldwide.

中文翻译：

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广谱抗生素佐剂可逆转多重耐药的革兰氏阴性病原体。

耐多药（MDR）细菌病原体的迅速出现和传播对全球医疗保健构成了严重威胁。一个特别令人担忧的问题是对碳青霉烯类耐药的肠杆菌科（CRE），这是一组革兰氏阴性细菌，已经对所有或几乎所有可用的抗生素产生了耐药性。加上当今抗生素开发渠道贫乏的事实，一种关键方法是使用抗生素佐剂来活化现有抗生素。我们发现了一种短的线性抗菌肽（SLAP）-S25，带有25个2,4-二氨基丁酸（Dab）的四个非天然氨基酸，仅显示出较弱的抗菌活性，但却提高了包括头孢吡肟在内的所有主要抗生素的疗效，大肠菌素，氧氟沙星，利福平，四环素和万古霉素，可抵抗MDR革兰氏阴性病原体。机理研究表明，SLAP-S25通过与外膜中的脂多糖（LPS）和细菌细胞质膜中的磷脂酰甘油（PG）结合而触发膜损伤，从而通过协同策略增强抗生素功效。最后，在三种动物模型中，SLAP-S25有效地提高了大肠菌素抵抗MDR大肠杆菌相关感染的活性。我们的发现提供了一种将现有抗生素与广谱抗生素佐剂结合使用的潜在治疗选择，以解决全球范围内由MDR革兰氏阴性病原体引起的普遍感染。通过协作策略增强抗生素功效。最后，在三种动物模型中，SLAP-S25有效地提高了大肠菌素抵抗MDR大肠杆菌相关感染的活性。我们的发现为将现有抗生素与广谱抗生素佐剂结合使用提供了潜在的治疗选择，以解决全球范围内由MDR革兰氏阴性病原体引起的普遍感染。通过协作策略增强抗生素功效。最后，在三种动物模型中，SLAP-S25有效地提高了大肠菌素抵抗MDR大肠杆菌相关感染的活性。我们的发现为将现有抗生素与广谱抗生素佐剂结合使用提供了潜在的治疗选择，以解决全球范围内由MDR革兰氏阴性病原体引起的普遍感染。