小菌落变异株的致病机制及治疗研究进展

doi:10.3969/j.issn.1674-8115.2025.06.014

摘要/Abstract

摘要：

小菌落变异株（small colony variant，SCV）是金黄色葡萄球菌等细菌在环境选择性压力下产生的特殊表型变异体，具有生长缓慢、色素合成减少、营养缺陷、耐药性增强以及易于细胞内定植和形成生物膜等独特的生物学特性。近年来，研究人员逐渐发现SCV在感染的慢性化进程和不良预后中扮演着关键角色。SCV群体表现出显著的异质性，其分子特征复杂多样。与野生型菌株相比，SCV毒力低下，黏附性显著增强，可有效逃避免疫系统的识别和清除。SCV通过侵入巨噬细胞等细胞内并形成无症状的休眠体，引起机体对抗菌药物耐药，在周围环境改善时可恢复为野生型细菌，造成骨髓炎、囊性纤维化、内植物感染等迁延不愈。但目前SCV治疗仅限于长期抗生素治疗联合感染部位清创处理，关于SCV及其致病机制与治疗认识依然不明确。传统疗法如利福平联合万古霉素对胞内SCV疗效有限，新型策略比如靶向ATP合酶抑制剂（如番茄红素）或纳米载体递送抗生素以增强胞内渗透、碱化微环境或者物理疗法破坏生物膜等将成为攻克SCV相关感染的重要突破口。该文总结了SCV的生物学特征、致病机制与治疗研究进展，为SCV相关感染的研究和治疗提供参考。

关键词: 小菌落变异株, 抗菌, 耐药性, 靶向感染

Abstract:

Small colony variants (SCVs) are unique phenotypic variants produced by bacteria such as Staphylococcus aureus under environmental selective pressure, with specific biological characteristics, including slow growth, reduced pigment synthesis, auxotrophy, enhanced drug resistance, and easier intracellular colonization and biofilm formation. In recent years, it has been increasingly recognized that SCVs play a crucial role in the chronic progression of infections and poor prognosis. SCVs exhibit significant heterogeneity with complex and diverse molecular profiles. Compared with wild-type strains, SCVs have low virulence and significantly enhanced adherence, and they can effectively evade immune system recognition and clearance. SCVs invade host cells, including macrophages, and form dormant intracellular forms, causing antimicrobial resistance. These variants can revert to wild-type bacteria when environmental conditions improve, causing persistent and refractory infections such as osteomyelitis, cystic fibrosis, and implant-associated infections. However, current treatments for SCV-related infections are limited to long-term antibiotic therapy combined with debridement of infected tissue, and understanding of SCVs, their pathogenic mechanisms, and treatments remains limited. Traditional therapies, such as rifampicin combined with vancomycin, have limited efficacy against intracellular SCVs. Novel strategies, such as targeting ATP synthase inhibitors (eg. lycopene), using nanocarrier-delivered antibiotics to enhance intracellular penetration, alkalinizing of the microenvironment, or disrupting biofilms by physical therapies, are important breakthroughs in the fight against SCV-associated infections. This paper summarizes the biological characteristics, pathogenic mechanisms, and therapeutic progress of SCVs, providing reference for research and treatment of SCV-related infections.

Key words: small colony variant (SCV), antibacterial, drug resistance, targeted infection

中图分类号:

R378.1

梁效宁, 石亭旺, 陈云丰. 小菌落变异株的致病机制及治疗研究进展[J]. 上海交通大学学报（医学版）, 2025, 45(6): 784-791.

LIANG Xiaoning, SHI Tingwang, CHEN Yunfeng. Pathogenic mechanisms and therapeutic advances of small colony variants[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(6): 784-791.

图/表 2

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Colony and cellular morphology	SCV	NP
Colony appearance	Small, transparent, needle-like in shape and irregular	Round, smooth, with intact edges, convex and glossy
Pigmentation	Reduced or absent	Colorless or colored (varies by species)
Hemolytic rings	Diameter reduced or absent	S. aureus exhibits α- or β-hemolysis
Size after 24 h culture	Invisible or tiny (1/10 the size of wild-type strains)	Visible to the naked eye, 1‒3 mm or larger
Special structure	PA-SCVs: fewer flagella, increased pil and thicker capsule	Normal
Cell shape	Incomplete, branched and cross-linked	Round
Cell wall	Thickened	Relatively thin
Cytoplasm	Homogeneous	Heterogeneous (high peripheral particle density, low central density)

Colony and cellular morphology	SCV	NP
Colony appearance	Small, transparent, needle-like in shape and irregular	Round, smooth, with intact edges, convex and glossy
Pigmentation	Reduced or absent	Colorless or colored (varies by species)
Hemolytic rings	Diameter reduced or absent	S. aureus exhibits α- or β-hemolysis
Size after 24 h culture	Invisible or tiny (1/10 the size of wild-type strains)	Visible to the naked eye, 1‒3 mm or larger
Special structure	PA-SCVs: fewer flagella, increased pil and thicker capsule	Normal
Cell shape	Incomplete, branched and cross-linked	Round
Cell wall	Thickened	Relatively thin
Cytoplasm	Homogeneous	Heterogeneous (high peripheral particle density, low central density)

Carrier type	Delivery vehicle	Loaded antibiotic	SCV infection model
Lipid Nanoparticles	Poly lactic-co-glycolic acid (PLGA) nanoparticles^[40]	Rifampin	Murine macrophage Sau-SCV infection model
Silica Nanoparticles	Mesoporous silica nanoparticles (MSNPs)^[41]	Rifampin	Murine macrophage Sau-SCV infection model
Silica Nanoparticles	Organically modified (ethylene-bridged) MSNPs (MONs)^[42]	Rifampin	Murine macrophage Sau-SCV infection model
Nanogels	Dual-responsive nanogels^[20]	Gentamicin	Mouse peritonitis model
Nanogels	Gelatin-alginate composite nanogels^[43]	Enrofloxacin	Sau-SCV strain
Nanogels	Chitosan oligosaccharide-carboxymethyl cellulose composite nanogels^[44]	Tilmicosin	Sau-SCV strain
Nanogels	Composite nanogels^[45]	Florfenicol	Murine mastitis model
Nanogels	Chitosan composite nanogels^[46]	Glycyrrhizic acid	Sau-SCV strain

Carrier type	Delivery vehicle	Loaded antibiotic	SCV infection model
Lipid Nanoparticles	Poly lactic-co-glycolic acid (PLGA) nanoparticles^[40]	Rifampin	Murine macrophage Sau-SCV infection model
Silica Nanoparticles	Mesoporous silica nanoparticles (MSNPs)^[41]	Rifampin	Murine macrophage Sau-SCV infection model
Silica Nanoparticles	Organically modified (ethylene-bridged) MSNPs (MONs)^[42]	Rifampin	Murine macrophage Sau-SCV infection model
Nanogels	Dual-responsive nanogels^[20]	Gentamicin	Mouse peritonitis model
Nanogels	Gelatin-alginate composite nanogels^[43]	Enrofloxacin	Sau-SCV strain
Nanogels	Chitosan oligosaccharide-carboxymethyl cellulose composite nanogels^[44]	Tilmicosin	Sau-SCV strain
Nanogels	Composite nanogels^[45]	Florfenicol	Murine mastitis model
Nanogels	Chitosan composite nanogels^[46]	Glycyrrhizic acid	Sau-SCV strain