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铜绿假单胞菌RSCVs的致病机制与临床干预研究进展
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Abstract:
铜绿假单胞菌(Pseudomonas aeruginosa)的皱缩型小菌落变异体(Rugose Small Colony Variants, RSCVs)是一种具有高生物被膜形成能力和高适应性的表型变异体，常在囊性纤维化患者的慢性感染分离株中被发现。其形成机制主要与环二鸟苷酸(c-di-GMP)信号通路的异常激活密切相关。本文系统地总结了RSCVs的分子机制、临床意义以及新型治疗策略，以期为RSCVs的基础研究与临床干预提供系统性参考。
Rugose Small Colony Variants (RSCVs) of Pseudomonas aeruginosa are phenotypic variants with high biofilm-forming capacity and adaptability, frequently identified in chronic infection isolates from patients with cystic fibrosis. Their formation is primarily associated with the abnormal activation of the cyclic diguanylate monophosphate (c-di-GMP) signaling pathway. This review systematically summarizes the molecular mechanisms, clinical significance, and novel therapeutic strategies of RSCVs, aiming to provide a comprehensive reference for the basic research and clinical intervention of RSCVs.
| [1] | Krell, T. and Matilla, M.A. (2024) Pseudomonas aeruginosa. Trends in Microbiology, 32, 216-218. https://doi.org/10.1016/j.tim.2023.11.005 |
| [2] | Drenkard, E. and Ausubel, F.M. (2002) Pseudomonas Biofilm Formation and Antibiotic Resistance Are Linked to Phenotypic Variation. Nature, 416, 740-743. https://doi.org/10.1038/416740a |
| [3] | Xu, A., Zhang, X., Wang, T., Xin, F., Ma, L.Z., Zhou, J., et al. (2021) Rugose Small Colony Variant and Its Hyper-Biofilm in Pseudomonas aeruginosa: Adaption, Evolution, and Biotechnological Potential. Biotechnology Advances, 53, Article ID: 107862. https://doi.org/10.1016/j.biotechadv.2021.107862 |
| [4] | Hengge, R. (2009) Principles of c-di-GMP Signalling in Bacteria. Nature Reviews Microbiology, 7, 263-273. https://doi.org/10.1038/nrmicro2109 |
| [5] | Römling, U., Galperin, M.Y. and Gomelsky, M. (2013) Cyclic di-GMP: The First 25 Years of a Universal Bacterial Second Messenger. Microbiology and Molecular Biology Reviews, 77, 1-52. https://doi.org/10.1128/mmbr.00043-12 |
| [6] | Jenal, U., Reinders, A. and Lori, C. (2017) Cyclic di-GMP: Second Messenger Extraordinaire. Nature Reviews Microbiology, 15, 271-284. https://doi.org/10.1038/nrmicro.2016.190 |
| [7] | O’Neal, L., Baraquet, C., Suo, Z., Dreifus, J.E., Peng, Y., Raivio, T.L., et al. (2022) The WSP System of Pseudomonas aeruginosa Links Surface Sensing and Cell Envelope Stress. Proceedings of the National Academy of Sciences of the United States of America, 119, e2117633119. https://doi.org/10.1073/pnas.2117633119 |
| [8] | Park, S. and Sauer, K. (2022) Controlling Biofilm Development through Cyclic di-GMP Signaling. In: Filloux, A. and Ramos, J.L., Eds., Pseudomonas aeruginosa, Springer International Publishing, 69-94. https://doi.org/10.1007/978-3-031-08491-1_3 |
| [9] | Xu, K., Wang, L., Xiong, D., Chen, H., Tong, X., Shao, X., et al. (2022) The WSP Chemosensory System Modulates C-di-GMP-Dependent Biofilm Formation by Integrating DSF Quorum Sensing through the WspR-RpfG Complex in Lysobacter. npj Biofilms and Microbiomes, 8, Article No. 97. https://doi.org/10.1038/s41522-022-00365-1 |
| [10] | Gloag, E.S., Marshall, C.W., Snyder, D., Lewin, G.R., Harris, J.S., Santos-Lopez, A., et al. (2019) Pseudomonas aeruginosa Interstrain Dynamics and Selection of Hyperbiofilm Mutants during a Chronic Infection. mBio, 10, e01698-19. https://doi.org/10.1128/mbio.01698-19 |
| [11] | O’Connor, J.R., Kuwada, N.J., Huangyutitham, V., Wiggins, P.A. and Harwood, C.S. (2012) Surface Sensing and Lateral Subcellular Localization of WSPA, the Receptor in a Chemosensory‐Like System Leading to C‐di‐GMP Production. Molecular Microbiology, 86, 720-729. https://doi.org/10.1111/mmi.12013 |
| [12] | Xu, A., Wang, D., Wang, Y., Zhang, L., Xie, Z., Cui, Y., et al. (2021) Mutations in Surface‐Sensing Receptor WSPA Lock the WSP Signal Transduction System into a Constitutively Active State. Environmental Microbiology, 24, 1150-1165. https://doi.org/10.1111/1462-2920.15763 |
| [13] | Xu, M., Yang, X., Yang, X., Zhou, L., Liu, T., Fan, Z., et al. (2016) Structural Insights into the Regulatory Mechanism of the Pseudomonas aeruginosa Yfibnr System. Protein & Cell, 7, 403-416. https://doi.org/10.1007/s13238-016-0264-7 |
| [14] | Malone, J.G., Jaeger, T., Manfredi, P., Dötsch, A., Blanka, A., Bos, R., et al. (2012) The Yfibnr Signal Transduction Mechanism Reveals Novel Targets for the Evolution of Persistent Pseudomonas aeruginosa in Cystic Fibrosis Airways. PLOS Pathogens, 8, e1002760. https://doi.org/10.1371/journal.ppat.1002760 |
| [15] | Malone, J.G., Jaeger, T., Spangler, C., Ritz, D., Spang, A., Arrieumerlou, C., et al. (2010) Yfibnr Mediates Cyclic Di-GMP Dependent Small Colony Variant Formation and Persistence in Pseudomonas aeruginosa. PLOS Pathogens, 6, e1000804. https://doi.org/10.1371/journal.ppat.1000804 |
| [16] | Brencic, A., McFarland, K.A., McManus, H.R., Castang, S., Mogno, I., Dove, S.L., et al. (2009) The GacS/GacA Signal Transduction System of Pseudomonas aeruginosa Acts Exclusively through Its Control over the Transcription of the RsmY and RsmZ Regulatory Small RNAs. Molecular Microbiology, 73, 434-445. https://doi.org/10.1111/j.1365-2958.2009.06782.x |
| [17] | Shang, L., Yan, Y., Zhan, Y., Ke, X., Shao, Y., Liu, Y., et al. (2021) A Regulatory Network Involving Rpo, Gac and Rsm for Nitrogen-Fixing Biofilm Formation by Pseudomonas stutzeri. NPJ Biofilms and Microbiomes, 7, Article No. 54. https://doi.org/10.1038/s41522-021-00230-7 |
| [18] | Irie, Y., Starkey, M., Edwards, A.N., Wozniak, D.J., Romeo, T. and Parsek, M.R. (2010) Pseudomonas aeruginosa Biofilm Matrix Polysaccharide Psl Is Regulated Transcriptionally by RpoS and Post‐Transcriptionally by RsmA. Molecular Microbiology, 78, 158-172. https://doi.org/10.1111/j.1365-2958.2010.07320.x |
| [19] | Brencic, A. and Lory, S. (2009) Determination of the Regulon and Identification of Novel mRNA Targets of Pseudomonas aeruginosa RsmA. Molecular Microbiology, 72, 612-632. https://doi.org/10.1111/j.1365-2958.2009.06670.x |
| [20] | Harrison, J.J., Almblad, H., Irie, Y., Wolter, D.J., Eggleston, H.C., Randall, T.E., et al. (2020) Elevated Exopolysaccharide Levels in Pseudomonas aeruginosa Flagellar Mutants Have Implications for Biofilm Growth and Chronic Infections. PLOS Genetics, 16, e1008848. https://doi.org/10.1371/journal.pgen.1008848 |
| [21] | Wu, D.C., Zamorano-Sánchez, D., Pagliai, F.A., Park, J.H., Floyd, K.A., Lee, C.K., et al. (2020) Reciprocal c-di-GMP Signaling: Incomplete Flagellum Biogenesis Triggers c-di-GMP Signaling Pathways That Promote Biofilm Formation. PLOS Genetics, 16, e1008703. https://doi.org/10.1371/journal.pgen.1008703 |
| [22] | Lind, P.A., Libby, E., Herzog, J. and Rainey, P.B. (2019) Predicting Mutational Routes to New Adaptive Phenotypes. eLife, 8, e38822. https://doi.org/10.7554/elife.38822 |
| [23] | Mukherjee, S. and Bassler, B.L. (2019) Bacterial Quorum Sensing in Complex and Dynamically Changing Environments. Nature Reviews Microbiology, 17, 371-382. https://doi.org/10.1038/s41579-019-0186-5 |
| [24] | O’Loughlin, C.T., Miller, L.C., Siryaporn, A., Drescher, K., Semmelhack, M.F. and Bassler, B.L. (2013) A Quorum-Sensing Inhibitor Blocks Pseudomonas aeruginosa Virulence and Biofilm Formation. Proceedings of the National Academy of Sciences of the United States of America, 110, 17981-17986. https://doi.org/10.1073/pnas.1316981110 |
| [25] | Valenza, G., Tappe, D., Turnwald, D., Frosch, M., König, C., Hebestreit, H., et al. (2008) Prevalence and Antimicrobial Susceptibility of Microorganisms Isolated from Sputa of Patients with Cystic Fibrosis. Journal of Cystic Fibrosis, 7, 123-127. https://doi.org/10.1016/j.jcf.2007.06.006 |
| [26] | Crémet, L., Leroy, A., Muller, D., Delanou, S., Burghelea, A., Broquet, A., et al. (2021) Antibiotic Resistance Heterogeneity and LasR Diversity within Pseudomonas aeruginosa Populations from Pneumonia in Intensive Care Unit Patients. International Journal of Antimicrobial Agents, 57, Article ID: 106341. https://doi.org/10.1016/j.ijantimicag.2021.106341 |
| [27] | Goltermann, L. and Tolker-Nielsen, T. (2017) Importance of the Exopolysaccharide Matrix in Antimicrobial Tolerance of Pseudomonas aeruginosa Aggregates. Antimicrobial Agents and Chemotherapy, 61, e02696-16. https://doi.org/10.1128/aac.02696-16 |
| [28] | Malone, J. (2015) Role of Small Colony Variants in Persistence of Pseudomonas aeruginosa Infections in Cystic Fibrosis Lungs. Infection and Drug Resistance, 8, 237-247. https://doi.org/10.2147/idr.s68214 |
| [29] | Bogut, A. and Magryś, A. (2021) The Road to Success of Coagulase-Negative Staphylococci: Clinical Significance of Small Colony Variants and Their Pathogenic Role in Persistent Infections. European Journal of Clinical Microbiology & Infectious Diseases, 40, 2249-2270. https://doi.org/10.1007/s10096-021-04315-1 |
| [30] | Reinhardt, A., Köhler, T., Wood, P., Rohner, P., Dumas, J., Ricou, B., et al. (2007) Development and Persistence of Antimicrobial Resistance in Pseudomonas aeruginosa: A Longitudinal Observation in Mechanically Ventilated Patients. Antimicrobial Agents and Chemotherapy, 51, 1341-1350. https://doi.org/10.1128/aac.01278-06 |
| [31] | Abdiali, A., Mohammadimehr, M. and Aghaalaei, Y. (2006) Bactericidal Activity of Various Antibiotics against Biofilm-Producing Pseudomonas aeruginosa. International Journal of Antimicrobial Agents, 27, 196-200. https://doi.org/10.1016/j.ijantimicag.2005.10.007 |
| [32] | Wozniak, D.J. and Keyser, R. (2004) Effects of Subinhibitory Concentrations of Macrolide Antibiotics on Pseudomonas aeruginosa. Chest, 125, 62S-69S. https://doi.org/10.1378/chest.125.2_suppl.62s |
| [33] | Hoffmann, N., Lee, B., Hentzer, M., Rasmussen, T.B., Song, Z., Johansen, H.K., et al. (2007) Azithromycin Blocks Quorum Sensing and Alginate Polymer Formation and Increases the Sensitivity to Serum and Stationary-Growth-Phase Killing of Pseudomonas aeruginosa and Attenuates Chronic P. aeruginosa Lung Infection in Cftr−/−mice. Antimicrobial Agents and Chemotherapy, 51, 3677-3687. https://doi.org/10.1128/aac.01011-06 |
| [34] | Hawas, S., Qin, J., Wiedbrauk, S., Fairfull-Smith, K. and Totsika, M. (2023) Preclinical Evaluation of Nitroxide-Functionalised Ciprofloxacin as a Novel Antibiofilm Drug Hybrid for Urinary Tract Infections. Antibiotics, 12, Article 1479. https://doi.org/10.3390/antibiotics12101479 |
| [35] | Alkawash, M.A., Soothill, J.S. and Schiller, N.L. (2006) Alginate Lyase Enhances Antibiotic Killing of Mucoid Pseudomonas aeruginosa in Biofilms. APMIS, 114, 131-138. https://doi.org/10.1111/j.1600-0463.2006.apm_356.x |
| [36] | Zhao, T. and Liu, Y. (2010) N-Acetylcysteine Inhibit Biofilms Produced by Pseudomonas aeruginosa. BMC Microbiology, 10, Article No. 140. https://doi.org/10.1186/1471-2180-10-140 |
| [37] | Eckhart, L., Fischer, H., Barken, K.B., Tolker-Nielsen, T. and Tschachler, E. (2007) DNase1L2 Suppresses Biofilm Formation by Pseudomonas aeruginosa and Staphylococcus aureus. British Journal of Dermatology, 156, 1342-1345. https://doi.org/10.1111/j.1365-2133.2007.07886.x |
| [38] | Qais, F.A., Khan, M.S., Ahmad, I., Husain, F.M., Arshad, M., Khan, A., et al. (2023) Modulation of Quorum Sensing and Biofilm of Gram‐Negative Bacterial Pathogens by Cinnamomum zeylanicum L. Microscopy Research and Technique, 87, 42-52. https://doi.org/10.1002/jemt.24410 |
| [39] | Roe, D., Karandikar, B., Bonn-Savage, N., Gibbins, B. and Roullet, J. (2008) Antimicrobial Surface Functionalization of Plastic Catheters by Silver Nanoparticles. Journal of Antimicrobial Chemotherapy, 61, 869-876. https://doi.org/10.1093/jac/dkn034 |
| [40] | Manner, C., Dias Teixeira, R., Saha, D., Kaczmarczyk, A., Zemp, R., Wyss, F., et al. (2023) A Genetic Switch Controls Pseudomonas aeruginosa Surface Colonization. Nature Microbiology, 8, 1520-1533. https://doi.org/10.1038/s41564-023-01403-0 |
| [41] | Oliveira, F., Rohde, H., Vilanova, M. and Cerca, N. (2021) The Emerging Role of Iron Acquisition in Biofilm-Associated Infections. Trends in Microbiology, 29, 772-775. https://doi.org/10.1016/j.tim.2021.02.009 |
| [42] | Kannon, M., Nebane, N.M., Ruiz, P., McKellip, S., Vinson, P.N. and Mitra, A. (2022) A Novel Approach to Identify Inhibitors of Iron Acquisition Systems of Pseudomonas aeruginosa. Microbiology Spectrum, 10, e0243722. https://doi.org/10.1128/spectrum.02437-22 |
| [43] | Cho, K.H., Tryon, R.G. and Kim, J. (2020) Screening for Diguanylate Cyclase (DGC) Inhibitors Mitigating Bacterial Biofilm Formation. Frontiers in Chemistry, 8, Article 264. https://doi.org/10.3389/fchem.2020.00264 |
| [44] | Andersen, J.B., Hultqvist, L.D., Jansen, C.U., Jakobsen, T.H., Nilsson, M., Rybtke, M., et al. (2021) Identification of Small Molecules That Interfere with c-di-GMP Signaling and Induce Dispersal of Pseudomonas aeruginosa Biofilms. npj Biofilms and Microbiomes, 7, Article No. 59. https://doi.org/10.1038/s41522-021-00225-4 |
| [45] | Xuan, T., Wang, Z., Liu, J., Yu, H., Lin, Q., Chen, W., et al. (2021) Design and Synthesis of Novel c-di-GMP G-Quadruplex Inducers as Bacterial Biofilm Inhibitors. Journal of Medicinal Chemistry, 64, 11074-11089. https://doi.org/10.1021/acs.jmedchem.1c00465 |
