Journal of Shanghai Jiao Tong University (Medical Science) >

2025 , Vol. 45 >Issue 6: 784 - 791

DOI: https://doi.org/10.3969/j.issn.1674-8115.2025.06.014

Review

Pathogenic mechanisms and therapeutic advances of small colony variants

  • LIANG Xiaoning ,
  • SHI Tingwang ,
  • CHEN Yunfeng
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  • Department of Orthopedic Surgery, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
First author contact:The manuscript was drafted and written by LIANG Xiaoning. The manuscript was revised and finalized by SHI Tingwang and CHEN Yunfeng. All authors have read the final version of the paper and consented to submission.
CHEN Yunfeng, E-mail: drchenyunfeng@sina.com.

Received date: 2025-02-17

  Accepted date: 2025-04-03

  Online published: 2025-06-28

Supported by

National Natural Science Foundation of China(82472464)

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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

Cite this article

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 . DOI: 10.3969/j.issn.1674-8115.2025.06.014

References

[1] SHI T W, WU Q, RUAN Z S, et al. Resensitizing β-lactams by reprogramming purine metabolism in small colony variant for osteomyelitis treatment[J]. Adv Sci (Weinh), 2025, 12(5): e2410781.
[2] ZHOU S Z, RAO Y F, LI J, et al. Staphylococcus aureus small-colony variants: formation, infection, and treatment[J]. Microbiol Res, 2022, 260: 127040.
[3] MAPAR M, RYDZAK T, HOMMES J W, et al. Diverse molecular mechanisms underpinning Staphylococcus aureus small colony variants[J]. Trends Microbiol, 2025, 33(2): 223-232.
[4] GIMZA B D, CASSAT J E. Mechanisms of antibiotic failure during Staphylococcus aureus osteomyelitis[J]. Front Immunol, 2021, 12: 638085.
[5] XU A M, ZHANG X X, WANG T, et al. Rugose small colony variant and its hyper-biofilm in Pseudomonas aeruginosa: adaption, evolution, and biotechnological potential[J]. Biotechnol Adv, 2021, 53: 107862.
[6] TSUJINO Y, OGAWA E, ITO K. Thymidine-dependent small-colony variants of Staphylococcus aureus isolated from infective endocarditis in a postlung transplant patient[J]. Transpl Infect Dis, 2024, 26(1): e14176.
[7] GOORMAGHTIGH F, VAN BAMBEKE F. Understanding Staphylococcus aureus internalisation and induction of antimicrobial tolerance[J]. Expert Rev Anti Infect Ther, 2024, 22(1/2/3): 87-101.
[8] GUéRILLOT R, KOSTOULIAS X, DONOVAN L, et al. Unstable chromosome rearrangements in Staphylococcus aureus cause phenotype switching associated with persistent infections[J]. Proc Natl Acad Sci USA, 2019, 116(40): 20135-20140.
[9] PROKOPCZUK F I, IM H, CAMPOS-GOMEZ J, et al. Engineered superinfective pf phage prevents dissemination of Pseudomonas aeruginosa in a mouse burn model[J]. mBio, 2023, 14(3): e0047223.
[10] TASHIRO Y, EIDA H, ISHII S, et al. Generation of small colony variants in biofilms by Escherichia coli harboring a conjugative F plasmid[J]. Microbes Environ, 2017, 32(1): 40-46.
[11] WONG FOK LUNG T, MONK I R, ACKER K P, et al. Staphylococcus aureus small colony variants impair host immunity by activating host cell glycolysis and inducing necroptosis[J]. Nat Microbiol, 2020, 5(1): 141-153.
[12] KWIECINSKI J M, HORSWILL A R. Staphylococcus aureus bloodstream infections: pathogenesis and regulatory mechanisms[J]. Curr Opin Microbiol, 2020, 53: 51-60.
[13] SHEYKHSARAN E, ABBASI A, MEMAR M Y, et al. The role of Staphylococcus aureus in cystic fibrosis pathogenesis and clinico-microbiological interactions[J]. Diagn Microbiol Infect Dis, 2024, 109(3): 116294.
[14] TOMAZ A P O, SOUZA D C, COGO L L, et al. Thymidine-dependent Staphylococcus aureus and lung function in patients with cystic fibrosis: a 10-year retrospective case-control study[J]. J Bras Pneumol, 2024, 50(4): e20240026.
[15] BURFORD-GORST C M, KIDD S P. Phenotypic variation in Staphylococcus aureus during colonisation involves antibiotic-tolerant cell types[J]. Antibiotics (Basel), 2024, 13(9): 845.
[16] LI X F, BUSCH L M, PIERSMA S, et al. Functional and proteomic dissection of the contributions of CodY, SigB and the hibernation promoting factor HPF to interactions of Staphylococcus aureus USA300 with human lung epithelial cells[J]. J Proteome Res, 2024, 23(10): 4742-4760.
[17] ALVES J, VRIELING M, RING N, et al. Experimental evolution of Staphylococcus aureus in macrophages: dissection of a conditional adaptive trait promoting intracellular survival[J]. mBio, 2024, 15(6): e0034624.
[18] STRAUB J, BAERTL S, VERHEUL M, et al. Antimicrobial resistance: biofilms, small colony variants, and intracellular bacteria[J]. Injury, 2024, 55(Suppl 6): 111638.
[19] JOSSE J, LAURENT F, DIOT A. Staphylococcal adhesion and host cell invasion: fibronectin-binding and other mechanisms[J]. Front Microbiol, 2017, 8: 2433.
[20] XIE S, LI Y, CAO W X, et al. Dual-responsive nanogels with cascaded gentamicin release and lysosomal escape to combat intracellular small colony variants for peritonitis and sepsis therapies[J]. Adv Healthc Mater, 2024, 13(14): e2303671.
[21] SEDLYAROV V, EICHNER R, GIRARDI E, et al. The bicarbonate transporter SLC4A7 plays a key role in macrophage phagosome acidification[J]. Cell Host Microbe, 2018, 23(6): 766-774.e5.
[22] VOLK C F, PROCTOR R A, ROSE W E. The complex intracellular lifecycle of Staphylococcus aureus contributes to reduced antibiotic efficacy and persistent bacteremia[J]. Int J Mol Sci, 2024, 25(12): 6486.
[23] MOLDOVAN A, FRAUNHOLZ M J. In or out: phagosomal escape of Staphylococcus aureus[J]. Cell Microbiol, 2019, 21(3): e12997.
[24] MAGRY? A, BOGUT A. microRNA hsa-let-7a facilitates staphylococcal small colony variants survival in the THP-1 macrophages by reshaping inflammatory responses[J]. Int J Med Microbiol, 2021, 311(8): 151542.
[25] GUO H N, TONG Y C, CHENG J H, et al. Biofilm and small colony variants-an update on Staphylococcus aureus strategies toward drug resistance[J]. Int J Mol Sci, 2022, 23(3): 1241.
[26] ZHENG X K, FANG R C, WANG C, et al. Resistance profiles and biological characteristics of rifampicin-resistant Staphylococcus aureus small-colony variants[J]. Infect Drug Resist, 2021, 14: 1527-1536.
[27] GOUNANI Z, KARAMAN D ?, VENU A P, et al. Coculture of P. aeruginosa and S. aureus on cell derived matrix: An in vitro model of biofilms in infected wounds[J]. J Microbiol Methods, 2020, 175: 105994.
[28] DOUGLAS E J A, DUGGAN S, BRIGNOLI T, et al. The MpsB protein contributes to both the toxicity and immune evasion capacity of Staphylococcus aureus[J]. Microbiology (Reading), 2021, 167(10): 001096.
[29] H?FFNER N, B?R J, DENGLER HAUNREITER V, et al. Intracellular environment and agr system affect colony size heterogeneity of Staphylococcus aureus[J]. Front Microbiol, 2020, 11: 1415.
[30] ZHOU K X, LI C, CHEN D M, et al. A review on nanosystems as an effective approach against infections of Staphylococcus aureus[J]. Int J Nanomedicine, 2018, 13: 7333-7347.
[31] CAMPBELL A J, DOTEL R, BRADDICK M, et al. Clindamycin adjunctive therapy for severe Staphylococcus aureus treatment evaluation (CASSETTE): an open-labelled pilot randomized controlled trial[J]. JAC Antimicrob Resist, 2022, 4(1): dlac014.
[32] SUBRAMANIAM S, JOYCE P, CONN C E, et al. Cellular uptake and in vitro antibacterial activity of lipid-based nanoantibiotics are influenced by protein Corona[J]. Biomater Sci, 2024, 12(13): 3411-3422.
[33] LANGLOIS J P, LAROSE A, BROUILLETTE E, et al. Mode of antibacterial action of tomatidine C3-diastereoisomers[J]. Molecules, 2024, 29(2): 343.
[34] VESTERGAARD M, ROSHANAK S, INGMER H. Targeting the ATP synthase in Staphylococcus aureus small colony variants, Streptococcus pyogenes and pathogenic fungi[J]. Antibiotics (Basel), 2021, 10(4): 376.
[35] BERBERICH C E, JOSSE J, LAURENT F, et al. Dual antibiotic loaded bone cement in patients at high infection risks in arthroplasty: rationale of use for prophylaxis and scientific evidence[J]. World J Orthop, 2021, 12(3): 119-128.
[36] JOOSTEN U, JOIST A, GOSHEGER G, et al. Effectiveness of hydroxyapatite-vancomycin bone cement in the treatment of Staphylococcus aureus induced chronic osteomyelitis[J]. Biomaterials, 2005, 26(25): 5251-5258.
[37] ENSING G T, VAN HORN J R, VAN DER MEI H C, et al. Copal bone cement is more effective in preventing biofilm formation than Palacos R-G[J]. Clin Orthop Relat Res, 2008, 466(6): 1492-1498.
[38] JAIKUMPUN P, RUKSAKIET K, STERCZ B, et al. Antibacterial effects of bicarbonate in media modified to mimic cystic fibrosis sputum[J]. Int J Mol Sci, 2020, 21(22): 8614.
[39] R?HRIG C, HUEMER M, LORGé D, et al. Targeting hidden pathogens: cell-penetrating enzybiotics eradicate intracellular drug-resistant Staphylococcus aureus[J]. mBio, 2020, 11(2): e00209-20.
[40] MAGHREBI S, JOYCE P, JAMBHRUNKAR M, et al. Poly(lactic- co-glycolic) acid-lipid hybrid microparticles enhance the intracellular uptake and antibacterial activity of rifampicin[J]. ACS Appl Mater Interfaces, 2020, 12(7): 8030-8039.
[41] JOYCE P, ULMEFORS H, MAGHREBI S, et al. Enhancing the cellular uptake and antibacterial activity of rifampicin through encapsulation in mesoporous silica nanoparticles[J]. Nanomaterials (Basel), 2020, 10(4): 815.
[42] JAMBHRUNKAR M, MAGHREBI S, DODDAKYATHANAHALLI D, et al. Mesoporous organosilica nanoparticles to fight intracellular staphylococcal aureus infections in macrophages[J]. Pharmaceutics, 2023, 15(4): 1037.
[43] LUO W H, LIU J H, ALGHARIB S A, et al. Antibacterial activity of enrofloxacin loaded gelatin-sodium alginate composite nanogels against intracellular Staphylococcus aureus small colony variants[J]. J Vet Sci, 2022, 23(3): e48.
[44] LUO W H, LIU J H, ZHANG S L, et al. Enhanced antibacterial activity of tilmicosin against Staphylococcus aureus small colony variants by chitosan oligosaccharide-sodium carboxymethyl cellulose composite nanogels[J]. J Vet Sci, 2022, 23(1): e1.
[45] LIU J H, JU M J, WU Y F, et al. Antibacterial activity of florfenicol composite nanogels against Staphylococcus aureus small colony variants[J]. J Vet Sci, 2022, 23(5): e78.
[46] JU M J, LIU J H, GUAN D, et al. WITHDRAWN: antibacterial activity of a novel glycyrrhizic acid-loaded chitosan composite nanogel in vitro against Staphylococcus aureus small colony variants[J]. Curr Drug Deliv, 2025.
[47] KARAMI A, FARIVAR F, DE PRINSE T J, et al. Facile multistep synthesis of ZnO-coated β-NaYF4: Yb/Tm upconversion nanoparticles as an antimicrobial photodynamic therapy for persistent Staphylococcus aureus small colony variants[J]. ACS Appl Bio Mater, 2021, 4(8): 6125-6136.
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