金黄色葡萄球菌耐药机制与新型治疗策略研究进展

doi:10.13560/j.cnki.biotech.bull.1985.2025-1032

摘要/Abstract

摘要：

金黄色葡萄球菌（Staphylococcus aureus）及其耐甲氧西林金黄色葡萄球菌（methicillin-resistant Staphylococcus aureus, MRSA）因强耐药性和高致病性，已成为全球抗生素耐药领域的核心问题之一。其耐药性由多重机制共同介导，包括mecA/mecC基因介导的PBP2a异常表达、耐药基因水平传播、生物膜形成以及持留细胞的产生。由于传统抗生素对耐药菌株的疗效受限，开发新型抗 S. aureus 感染策略已成为临床及科研领域的重要方向。纳米抗菌疗法通过靶向递送和多靶点杀菌机制，在克服细菌耐药性方面显示出潜力；抗菌肽因广谱抗菌活性和低耐药诱导风险而备受关注；噬菌体疗法、噬菌体裂解酶及免疫疗法等替代方案也取得了重要的研究进展。然而，这些新策略在走向临床应用时，仍面临毒性、稳定性及潜在耐药传播风险等挑战。未来研究需聚焦于递药系统优化、靶向精确性提升与毒副作用控制，进一步解析耐药动态演化机制，推动安全有效的抗感染策略的临床转化，最终实现对S. aureus感染的有效控制。

关键词: 金黄色葡萄球菌, 耐甲氧西林金黄色葡萄球菌, 耐药机制, 新型治疗策略

Abstract:

Staphylococcus aureus and its methicillin-resistant strains (MRSA) have become one of the central challenges in the global fight against antibiotic resistance due to their strong multidrug resistance and high pathogenicity. The resistance of S. aureus is mediated by multiple mechanisms, including aberrant expression of PBP2a encoded by the mecA/mecC genes, horizontal transfer of resistance determinants, biofilm formation, and the generation of persister cells. Given the limited efficacy of conventional antibiotics against resistant strains, developing novel strategies to combat S. aureus infections has become a key focus in both clinical and research fields. Nanotechnology-based antimicrobial therapies have demonstrated great potential in overcoming bacterial resistance through targeted delivery and multi-target bactericidal mechanisms. Antimicrobial peptides, with their broad-spectrum activity and low risk of resistance induction, have attracted increasing attention, while alternative approaches such as bacteriophage therapy, phage-derived lysins, and immunotherapy have also achieved significant progress. However, the clinical translation of these emerging strategies remains challenged by issues of toxicity, stability, and the potential risk of resistance dissemination. Future research should focus on optimizing drug delivery systems, enhancing targeting precision, and minimizing adverse effects, while further elucidating the dynamic mechanisms underlying resistance evolution, to promote the safe and effective clinical translation of anti-infective strategies and ultimately achieve effective control of S. aureus infections.

Key words: Staphylococcus aureus, MRSA, drug resistance mechanisms, novel therapeutic strategies

王羽, 何昀珈, 殷海欣, 马悦, 郭海勇. 金黄色葡萄球菌耐药机制与新型治疗策略研究进展[J]. 生物技术通报, 2026, 42(4): 53-64.

WANG Yu, HE Yun-jia, YIN Hai-xin, MA Yue, GUO Hai-yong. Research Progress in Drug Resistance Mechanisms and Novel Therapeutic Strategies of Staphylococcus aureus[J]. Biotechnology Bulletin, 2026, 42(4): 53-64.

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治疗策略 Therapeutic strategy	疗效 Efficacy	安全性 Safety	耐药风险 Drug resistance risk	临床可行性 Clinical feasibility
纳米药物 Nanodrugs	通过靶向递送、增强穿透及多靶机制可显著提高抗菌活性并改善局部暴露^［47-51］	金属NPs可导致氧化应激与组织累积，而脂质体或聚合物载体毒性较低但需评估其体内清除途径与潜在免疫反应^［70-71］	相对较低，但长期低剂量暴露和亚抑制浓度可能诱导细菌耐受性或交叉抗性^［72-73］	工艺放大、批次一致性、长期安全性与监管审批是主要障碍^［74-75］；局部给药应用前景较好，系统给药需进一步评估^［44］
AMPs及其模拟物 AMPs and their mimetics	环化或脂肪化修饰的肽以及具有β-发夹结构的肽在体外对S. aureus和MRSA表现出显著抗菌活性^［76-78］	天然肽常表现出溶血和细胞毒性，化学修饰可降低毒性和延长半衰期，需系统评价免疫原性与代谢产物安全性^［79-80］	一般较低，但特异性选择压力及膜成分改变可能驱动耐受性，需要长期和体内进化实验验证^［81-82］	局部适应症优先，全身应用面临给药、稳定性和成本挑战，部分肽类已进入临床试验阶段^［83-85］
噬菌体疗法 Phage therapy	对特定菌株有高效裂解能力，可清除宿主细胞内或生物膜内相关菌株，但需针对性筛选噬菌体^［86］	总体良好，但噬菌体裂解可释放内毒素，且宿主免疫反应可能影响疗效与重复给药效果^［86］	细菌可通过受体变异等获得抗噬菌体性，但可通过噬菌体鸡尾酒或与抗生素联用来延缓抗性发展^［86］	在同情用药/个案治疗中已有成功记录，规模化推广需解决标准化与生产问题^［86］
噬菌体裂解酶 Phage lysin	能迅速裂解革兰阳性菌细胞壁，体外及动物模型显示显著杀菌效果^［87-88］	总体良好，但可能诱导宿主产生中和抗体，影响后续给药疗效，需评估其免疫原性^［89］	表现出较低的耐药倾向^［90］	在多种动物感染模型中展现出良好的抗菌疗效，并显示出在皮肤和消化道等特定部位局部应用的潜力^［87］
抗毒力疗法 Anti-virulence therapy	不直接杀菌，可抑制关键毒力因子的功能，减轻组织损伤和炎症，有助于降低致死风险^［91］	理论上选择压力低且可降低致病性，但需关注脱靶效应与免疫相关并发症^［92］	相对较低，但关键毒力位点突变仍可导致疗效下降^［93］	单药替代治疗证据不足，适合与抗菌药物联合使用，临床开发存在适应症界定与终点设计难题^［94］
靶向宿主免疫系统的疗法 Host immune system-targeted therapy	通过增强宿主清除能力或恢复免疫稳态，可促进病原体清除并降低复发风险^［95］	存在免疫相关不良反应，需谨慎评估给药窗口与患者适应症^［95］	不直接施加抗菌选择压力，理论上可降低耐药产生风险^［95］	疫苗与免疫调节剂在特定适应证中具有前景；开发中面临免疫异质性、长期安全性评估与终点确定挑战^［96-97］

治疗策略 Therapeutic strategy	疗效 Efficacy	安全性 Safety	耐药风险 Drug resistance risk	临床可行性 Clinical feasibility
纳米药物 Nanodrugs	通过靶向递送、增强穿透及多靶机制可显著提高抗菌活性并改善局部暴露^［47-51］	金属NPs可导致氧化应激与组织累积，而脂质体或聚合物载体毒性较低但需评估其体内清除途径与潜在免疫反应^［70-71］	相对较低，但长期低剂量暴露和亚抑制浓度可能诱导细菌耐受性或交叉抗性^［72-73］	工艺放大、批次一致性、长期安全性与监管审批是主要障碍^［74-75］；局部给药应用前景较好，系统给药需进一步评估^［44］
AMPs及其模拟物 AMPs and their mimetics	环化或脂肪化修饰的肽以及具有β-发夹结构的肽在体外对S. aureus和MRSA表现出显著抗菌活性^［76-78］	天然肽常表现出溶血和细胞毒性，化学修饰可降低毒性和延长半衰期，需系统评价免疫原性与代谢产物安全性^［79-80］	一般较低，但特异性选择压力及膜成分改变可能驱动耐受性，需要长期和体内进化实验验证^［81-82］	局部适应症优先，全身应用面临给药、稳定性和成本挑战，部分肽类已进入临床试验阶段^［83-85］
噬菌体疗法 Phage therapy	对特定菌株有高效裂解能力，可清除宿主细胞内或生物膜内相关菌株，但需针对性筛选噬菌体^［86］	总体良好，但噬菌体裂解可释放内毒素，且宿主免疫反应可能影响疗效与重复给药效果^［86］	细菌可通过受体变异等获得抗噬菌体性，但可通过噬菌体鸡尾酒或与抗生素联用来延缓抗性发展^［86］	在同情用药/个案治疗中已有成功记录，规模化推广需解决标准化与生产问题^［86］
噬菌体裂解酶 Phage lysin	能迅速裂解革兰阳性菌细胞壁，体外及动物模型显示显著杀菌效果^［87-88］	总体良好，但可能诱导宿主产生中和抗体，影响后续给药疗效，需评估其免疫原性^［89］	表现出较低的耐药倾向^［90］	在多种动物感染模型中展现出良好的抗菌疗效，并显示出在皮肤和消化道等特定部位局部应用的潜力^［87］
抗毒力疗法 Anti-virulence therapy	不直接杀菌，可抑制关键毒力因子的功能，减轻组织损伤和炎症，有助于降低致死风险^［91］	理论上选择压力低且可降低致病性，但需关注脱靶效应与免疫相关并发症^［92］	相对较低，但关键毒力位点突变仍可导致疗效下降^［93］	单药替代治疗证据不足，适合与抗菌药物联合使用，临床开发存在适应症界定与终点设计难题^［94］
靶向宿主免疫系统的疗法 Host immune system-targeted therapy	通过增强宿主清除能力或恢复免疫稳态，可促进病原体清除并降低复发风险^［95］	存在免疫相关不良反应，需谨慎评估给药窗口与患者适应症^［95］	不直接施加抗菌选择压力，理论上可降低耐药产生风险^［95］	疫苗与免疫调节剂在特定适应证中具有前景；开发中面临免疫异质性、长期安全性评估与终点确定挑战^［96-97］