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Aerobactin, but Not Yersiniabactin, Salmochelin, or Enterobactin, Enables the Growth/Survival of Hypervirulent (Hypermucoviscous) Klebsiella pneumoniae Ex Vivo and In Vivo
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The siderophore aerobactin is the dominant siderophore produced by hypervirulent Klebsiella pneumoniae (hvKP) and was previously shown to be a major virulence factor in systemic infection. However, strains of hvKP commonly produce the additional siderophores yersiniabactin, salmochelin, and enterobactin. The roles of these siderophores in hvKP infection have not been optimally defined. To that end, site-specific gene disruptions were created in hvKP1 (wild type), resulting in the generation of hvKP1Δ iucA (aerobactin deficient), hvKP1Δ iroB (salmochelin deficient), hvKP1Δ entB (enterobactin and salmochelin deficient), hvKP1Δ irp2 (yersiniabactin deficient), and hvKP1Δ entB Δ irp2 (enterobactin, salmochelin, and yersiniabactin deficient). The growth/survival of these constructs was compared to that of their wild-type parent hvKP1 ex vivo in human ascites fluid, human serum, and human urine and in vivo in mouse systemic infection and pulmonary challenge models. Interestingly, in contrast to aerobactin, the inability to produce enterobactin, salmochelin, or yersiniabactin individually or in combination did not decrease the ex vivo growth/survival in human ascites or serum or decrease virulence in the in vivo infection models. Surprisingly, none of the siderophores increased growth in human urine. In human ascites fluid supplemented with exogenous siderophores, siderophores increased the growth of hvKP1Δ iucA , with the relative activity being enterobactin > aerobactin > yersiniabactin > salmochelin, suggesting that the contribution of aerobactin to virulence is dependent on both innate biologic activity and quantity produced. Taken together, these data confirm and extend a role for aerobactin as a critical virulence factor for hvKP. Since it appears that aerobactin production is a defining trait of hvKP strains, this factor is a potential antivirulence target.
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“The elaboration and acquisition of the latter three siderophores are associated with the pathogenesis and hypervirulence of K. pneumoniae (1,44,53,54).”
From Siderophore-mediated iron acquisition by Klebsiella pneumoniae (2024) · cites this paper as [54]
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“However, unlike FeEnt, FeAbn uptake was not inhibited by SCN, reinforcing its importance in the pathogenesis of hvKp1 (54).”
From Siderophore-mediated iron acquisition by Klebsiella pneumoniae (2024) · cites this paper as [54]
Experimental — accuracy not yet measuredIn the citing paper
“The glucosylated ferric catecholate does not adsorb well to siderocalin ( Kumar et al., 2022 ), which promotes the pathogenesis of clinical isolates of E. coli, K. pneumoniae, and Salmonella typhimurium in human and animal hosts ( Russo et al., 2011 , 2015 ).”
From Specificity and mechanism of TonB-dependent ferric catecholate uptake by Fiu (2024) · cites this paper as Russo et al., 2015
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“Aerobactin is a critical virulence factor often found in hyper-virulent K. pneumoniae strains but rare in classical strains [34, 42, 90, 95, 106, 107].”
Marcoleta, A. E., Varas, M. A., Ortíz-Severín, J., Vásquez, L., Berríos-Pastén, C., Sabag, A., Chávez, F. P., Allende, M. L., Santiviago, C. A., Monasterio, O., et al. (2018) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2018.00030 · Cited by 44
“Regarding salmochelin production, a previous work with hypervirulent K. pneumoniae showed that aerobactin but not yersiniabactin, salmochelin, or enterobactin, were required for virulence over in vivo infection models (Russo et al., 2015).”
BackgroundWeber, B. S., Jong, A. M. D., Guo, A. B. Y., Dharavath, S., French, S., Fiebig‐Comyn, A., Coombes, B. K., Magolan, J., & Brown, E. D. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107927 · Cited by 44
Innate Host Defense against Klebsiella pneumoniae and the Outlook for Development of Immunotherapies
Opoku‐Temeng, C., Małachowa, N., Kobayashi, S. D., & DeLeo, F. R. (2021) · Journal of Innate Immunity · doi:10.1159/000518679 · Cited by 45
Siderophore-mediated iron acquisition by Klebsiella pneumoniae
Kumar, A., Chakravorty, S., Yang, T., Russo, T. A., Newton, S. M., & Klebba, P. E. (2024) · Journal of Bacteriology · doi:10.1128/jb.00024-24 · Cited by 42
“The elaboration and acquisition of the latter three siderophores are associated with the pathogenesis and hypervirulence of K. pneumoniae (1, 44, 53, 54).”
BackgroundSelf-citationTian, D., Wang, W., Li, M., Chen, W., Zhou, Y., Huang, Y., Sheng, Z.-K., & Jiang, X. (2021) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2021.752011 · Cited by 42
“Aerobactin is a critical virulence factor for hvKp, while the additional siderophores are not major contributors to high siderophore levels (Russo et al., 2015).”
BackgroundMai, D., Wu, A., Li, R., Cai, D., Tong, H., Wang, N., & Tan, J. (2023) · BMC Microbiology · doi:10.1186/s12866-023-03124-0 · Cited by 41
“Such as iuc (siderophore aerobic actin biosynthesis gene) [13], iro (salmonella bio-synthesis gene) [14], peg-344 (a metabolic transporter of unknown function) [15], rmpA and rmpA2 (a regulator that promotes capsule production) [16].”
BackgroundClinical and laboratory insights into the threat of hypervirulent Klebsiella pneumoniae
Han, X., Yao, J., He, J., Liu, H., Jiang, Y., Zhao, D., Shi, Q., Zhou, J., Hu, H., Lan, P., et al. (2024) · International Journal of Antimicrobial Agents · doi:10.1016/j.ijantimicag.2024.107275 · Cited by 43
Getting hypervirulent Klebsiella pneumoniae on the radar screen
Sellick, J. A., & Russo, T. A. (2018) · Current Opinion in Infectious Diseases · doi:10.1097/qco.0000000000000464 · Cited by 40
Self-citationMolecular validation of clinical Pantoea isolates identified by MALDI-TOF
Soutar, C. D., & Stavrinides, J. (2019) · PLoS ONE · doi:10.1371/journal.pone.0224731 · Cited by 40
“Aerobactin is a known virulence factor and has been demonstrated to be essential for the virulence of hypervirulent, Klebsiella pneumoniae [58,59].”
BackgroundSedighi, P., Zarei, O., Karimi, K., Taheri, M., Karami, P., & Shokoohizadeh, L. (2020) · International Journal of Microbiology · doi:10.1155/2020/8894727 · Cited by 40
Dereeper, A., Gruel, G., Pot, M., Couvin, D., Barbier, E., Bastian, S., Bambou, J., Gelu‐Siméon, M., Ferdinand, S., Guyomard-Rabenirina, S., et al. (2022) · Microbiology Spectrum · doi:10.1128/spectrum.01242-22 · Cited by 40
“nantly to hypervirulence in laboratory experiments and mouse models of disease, while the inactivation of other siderophore systems has minimal effects (35, 36).”
BackgroundAlharbi, M. T., Almuhayawi, M. S., Nagshabandi, M. K., Tarabulsi, M. K., Alruhaili, M. H., Gattan, H. S., Jaouni, S. K. A., Selim, S., Alanazi, A., Alruwaili, Y. S., et al. (2023) · Microorganisms · doi:10.3390/microorganisms11030661 · Cited by 38
“icuA Forward Reverse 5′-GCATAGGCGGATACGAACAT-3′ [10] 5′-CACAGGGCAATTGCTTACCT-3′”
The pathogenicity of rmpA or aerobactin-positive Klebsiella pneumoniae in infected mice
Li, G., Sun, S., Zhao, Z. Y., & Sun, Y. (2019) · Journal of International Medical Research · doi:10.1177/0300060519863544 · Cited by 38
Huang, Y., Li, J., Wang, Q., Tang, K., Cai, X., & Li, C. (2022) · Journal of Hospital Infection · doi:10.1016/j.jhin.2022.09.014 · Cited by 37
Royer, G., Clermont, O., Marin, J., Condamine, B., Dion, S., Blanquart, F., Galardini, M., & Denamur, É. (2023) · Nature Communications · doi:10.1038/s41467-023-39428-y · Cited by 38
“Aerobactin but not yersiniabactin or salmochelin enables survival of hypervirulent Klebsiella pneumoniae in mouse systemic infection 59 and the sit operon is required for systemic stages of infection in Salmonella Typhimurium 60 and Yersinia pestis 61 .”
BackgroundBailey, D. C., Drake, E. J., Grant, T. D., & Gulick, A. M. (2016) · Biochemistry · doi:10.1021/acs.biochem.6b00409 · Cited by 39
Aerobactin Synthesis Proteins as Antivirulence Targets in Hypervirulent Klebsiella pneumoniae
Russo, T. A., & Gulick, A. M. (2019) · ACS Infectious Diseases · doi:10.1021/acsinfecdis.9b00117 · Cited by 37
Self-citationInterplay between siderophores and colibactin genotoxin in Escherichia coli
Martín, P., Tronnet, S., Garcie, C., & Oswald, É. (2017) · IUBMB Life · doi:10.1002/iub.1612 · Cited by 38
“pneumoniae results in an attenuated virulence phenotype in a diversity of models of infection (13).”
BackgroundRadisic, V., Grevskott, D. H., Lunestad, B. T., Øvreås, L., & Marathe, N. P. (2022) · International Journal of Hygiene and Environmental Health · doi:10.1016/j.ijheh.2022.114075 · Cited by 33
Sherif, M. M., Palmieri, M., Mirande, C., El‐Mahallawy, H. A., Rashed, H. G., Reheem, F. A. E., Elmanakhly, A. R., Rabea, R. A., Aboulela, A., Saeed, L. Y., et al. (2021) · European Journal of Clinical Microbiology & Infectious Diseases · doi:10.1007/s10096-021-04177-7 · Cited by 36
Silvester, R., Madhavan, A., Kokkat, A., Parolla, A., Adarsh, B. M., Harikrishnan, M., & Abdulla, M. H. (2021) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2021.149859 · Cited by 38
Wu, X., Shi, Q., Shen, S., Huang, C., & Wu, H. (2021) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2021.688989 · Cited by 38
Virulence Factors and Carbapenem-Resistance Mechanisms in Hypervirulent Klebsiella Pneumoniae
Liao, Y., Gong, J., Yuan, X., Wang, X., Huang, Y., & Chen, X. (2024) · Infection and Drug Resistance · doi:10.2147/idr.s461903 · Cited by 34
“53 Disrupting the synthesis of aerobactin could thus reduce the growth or viability of hvKP in human ascites and serum, while disruption of enterobactin, yersiniabactin, and salmochelin synthesis cannot achieve the same effect, indicating that aerobactin is a key virulence factor in hvKP.”
BackgroundWang, T.-C., Lin, J., Chang, J.-C., Hiaso, Y.-W., Wang, C.-H., Chiu, S., Fung, C., Chang, F., & Siu, L.-K. K. (2021) · Gut Pathogens · doi:10.1186/s13099-021-00439-z · Cited by 34
“Aerobactin has been suggested to play an important role in virulence and is also a key biomarker of the enhancement of the growth and survival of HvKp [23, 31].”
BackgroundDu, P., Liu, C., Fan, S., Baker, S. G., & Guo, J. X. (2022) · Microbiology Spectrum · doi:10.1128/spectrum.01929-21 · Cited by 35
Huang, N., Jia, H., Zhou, B., Zhou, C., Cao, J., Liao, W., Liu, S., Wang, L., Chen, L., Chen, L., et al. (2022) · Frontiers in Public Health · doi:10.3389/fpubh.2022.991306 · Cited by 36
“pneumoniae growth and virulence in the host via regulation of iron supply, which could serve as a potential anti-virulence target (34, 37), and our study found that up to 66.”
BackgroundTsui, C. K. M., Abid, F. B., Ismail, K. A., McElheny, C. L., Maslamani, M. A. R. S. A., Omrani, A. S., & Doi, Y. (2023) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00030-23 · Cited by 34
“lator, encoded by rmpA, and aerobactin (12, 13).”
BackgroundYu, F., Lv, J., Niu, S., Du, H., Tang, Y., Bonomo, R. A., Kreiswirth, B. N., & Chen, L. (2018) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01031-18 · Cited by 32
Fluorescent sensors of siderophores produced by bacterial pathogens
Kumar, A., Yang, T., Chakravorty, S., Majumdar, A., Nairn, B. L., Six, D. A., Marcondes dos Santos, N., Price, S. L., Lawrenz, M. B., Actis, L. A., et al. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.101651 · Cited by 28
“pneumoniae (HvKp1, HvKp2 (39)) in iron-deficient MOPS (85) and M9 (86) minimal media, removed the cells by centrifugation, and analyzed the supernatants with decoy sensors.”
BackgroundMethodInfluentialSelf-citationRolbiecki, D., Harnisz, M., Korzeniewska, E., Buta, M., Hubeny, J., & Zieliński, W. (2021) · International Journal of Hygiene and Environmental Health · doi:10.1016/j.ijheh.2021.113831 · Cited by 33
Metadata
- Authors
- Russo, T. A., Olson, R., MacDonald, U., Beanan, J., & Davidson, B. A.
- Affiliations
- VA Western New York Healthcare System (US)
- Venue
- Infection and Immunity
- Publisher
- American Society for Microbiology
- Published
- 2015-08
- Volume
- 83
- Issue
- 8
- Pages
- 3325-3333
- ISSN
- 0019-9567 (ISSN-L)
- 1098-5522
- PMC
- PMC4496593
- OpenAlex
- W2283434174
- Semantic Scholar
- e716de1372bc2153e94e76130028b8b30a86c6b0
- Cited by
- 305
- References
- 49
- Citations by year
- 2026: 32 · 2025: 32 · 2024: 34 · 2023: 33 · 2022: 56 · 2021: 28 · 2020: 25 · 2019: 16 · 2018: 24 · 2017: 11 · 2016: 13 · 2015: 1
- FWCI
- 12.66
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Infection and Immunity (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs
- National Institutes of Health (W81XWH)
- National Institute of Allergy and Infectious Diseases (R21AI088318)
- Telemedicine and Advanced Technology Research Center
- Topics
- Life Sciences › Immunology and Microbiology › Microbiology › Escherichia coli research studies
- Life Sciences › Immunology and Microbiology › Microbiology › Enterobacteriaceae and Cronobacter Research
- Health Sciences › Medicine › Microbiology (medical) › Antibiotic Resistance in Bacteria
- Keywords
- aerobactin, yersiniabactin, salmochelin, enterobactin, siderophores, hypervirulent Klebsiella pneumoniae, hypermucoviscous Klebsiella pneumoniae, virulence factors, iron acquisition, iucA, IRP2, entB, iroB, systemic infection, pulmonary infection, ascitic fluid, human serum, human urine
- MeSH terms
- Animals, Enterobactin, Glucosides, Humans, Hydroxamic Acids, Klebsiella Infections, Klebsiella pneumoniae, Male, Phenols, Thiazoles, Virulence, Siderophores, Microbial Viability, Mice, Young Adult
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