混合生物膜的感染与治疗最新研究进展

Recent Research Advances in Infection and Treatment of Hybrid Biofilms

摘要: 混合生物膜感染是一种由多种微生物共存并形成生物膜的复杂感染类型，在慢性伤口、肺部感染、医疗器械相关感染等临床场景中极为常见。由于生物膜的胞外基质(Extracellular Polymeric Substances, EPS)屏障、持留菌、微生物相互保护作用、耐药基因水平传播等因素，混合生物膜感染对抗生素表现出极强的耐受性，导致治疗困难、感染反复发作，并使全球抗生素耐药问题进一步恶化。传统抗生素自青霉素发现以来，在感染治疗中发挥了重要作用。然而，在治疗混合生物膜感染时，传统抗生素存在药物穿透受限、持留菌耐受、微生物间协同耐药、群体感应(Quorum sensing, QS)调控耐药性等诸多缺陷。例如，β-内酰胺类抗生素因EPS屏障作用难以到达深层细菌，氨基糖苷类抗生素由于正电荷特性难以扩散，而喹诺酮类抗生素易诱导耐药突变。此外，混合生物膜中的细菌可以通过基因水平转移(horizontal gene transfer, HGT)迅速传播耐药基因，使联合抗生素疗法的效果受限，甚至可能加速耐药菌的进化。由于传统抗生素的局限性，混合生物膜感染的治疗面临极大挑战。因此，未来的研究方向应集中在新型抗菌策略上，包括纳米药物递送系统、生物膜靶向抗菌药物、噬菌体疗法、抗生物膜酶治疗、免疫调控疗法等，以期有效破坏混合生物膜结构，提高抗感染治疗的成功率。

Abstract: Mixed biofilm infection is a complex type of infection in which multiple microorganisms coexist and form a biofilm, which is extremely common in clinical scenarios such as chronic wounds, pulmonary infections, and medical device-related infections. Due to factors such as the Extracellular Polymeric Substances (EPS) barrier of biofilms, holding bacteria, mutual protective effects of microorganisms, and transmission of drug-resistant genes at the horizontal level, mixed biofilm infections show extreme resistance to antibiotics, leading to treatment difficulties, recurrent infections, and further worsening the global antibiotic resistance problem. Conventional antibiotics have played an important role in the treatment of infections since the discovery of penicillin. However, in the treatment of mixed biofilm infections, traditional antibiotics have many shortcomings, such as limited drug penetration, tolerance of holdout bacteria, synergistic resistance among microorganisms, and resistance modulation by quorum sensing (QS). For example, β-lactam antibiotics are difficult to reach deep bacteria due to the EPS barrier, aminoglycoside antibiotics are difficult to diffuse due to the positive charge property, and quinolone antibiotics are prone to induce drug resistance mutations. In addition, bacteria in mixed biofilms can rapidly spread drug-resistant genes through horizontal gene transfer (HGT), which limits the effectiveness of combination antibiotic therapy and may even accelerate the evolution of drug-resistant bacteria. The treatment of mixed biofilm infections is extremely challenging due to the limitations of conventional antibiotics. Therefore, future research should focus on novel antimicrobial strategies, including nano drug delivery systems, biofilm-targeted antimicrobials, phage therapy, anti-biofilm enzyme therapy, and immunomodulatory therapy, with the aim of effectively destroying the structure of mixed biofilms and improving the success rate of anti-infective treatments.