Iron Metabolism at the Interface between Host and Pathogen: From Nutritional Immunity to Antibacterial Development
Abstract
1. Iron and Nutritional Immunity
1.1. Iron: A Double-Edged Sword
1.2. The Mechanisms of Nutritional Immunity
1.3. Nutritional Immunity under Infection Conditions
2. Mechanisms of Iron Acquisition by Staphylococcus aureus
2.1. Siderophores
2.1.1. Endogenous Siderophores
Carboxylate-Type Siderophores: Staphyloferrin A and Staphyloferrin B
Other Endogenous Iron-Chelators
2.1.2. Exogenous Siderophores
2.2. Hemic Iron
2.2.1. Hemolysins and Leukocidins
2.2.2. Isd System
Isd in Heme Uptake
Isd Moonlighting Activities
2.2.3. Fep System
2.3. Heme and Iron Homeostasis inside S. aureus
3. Effects of Iron Restriction and Mutations of Assimilatory Pathways on Fitness and Virulence
4. Antibiotic Strategies Targeting Iron Uptake in S. aureus - Small Molecules
4.1. Targeting Pre-Iron-Uptake Systems
4.1.1. Quorum Sensing Inhibitors
4.1.2. Small Molecules as Hemolysin Inhibitors
4.1.3. Iron Chelators
4.2. Targeting the Iron-Uptake Systems
4.2.1. Exploiting the Iron-Uptake System
Trojan Horses
Gallium-Derivatives
4.2.2. Inhibiting the Iron-Uptake System
Inhibitors of Siderophore Biosynthesis
4.3. Targeting the Post-Iron-Uptake Metabolism
Heme Oxygenase Inhibitors
5. Biopharmaceutical Approaches Targeting the Iron System in S. aureus
5.1. Biologics Targeting the Staphylococcal Iron/Heme Uptake Systems
5.2. Biologics Targeting Staphylococcal Hemolysins
6. Conclusions
Funding
Acknowledgments
Conflicts of Interest
References
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PDB Codes | Protein | Reference |
---|---|---|
3lhs, 3li2 | HtsA | [57] |
3eiw, 3eix | HtsA | [58] |
5d84, 5d85 | SbnA | [59] |
4m54, 4mp3, 4mp6, 4mp8, 4mpd | SbnB | [60] |
4tv5 | SbnG | [61] |
5uje | SbnI | [62] |
6knh and 6kni | SbnH | [63] |
3mwf, 3mwg | SirA | [64] |
4fna, 4fil | FhuD2 | [65] |
4b8y | FhuD2 | [66] |
5twb, 5twc | IruO | [67] |
7ahl | Hla | [68] |
3b07 | Hlg | [69] |
4q7g | LukD | [70] |
3roh | LukE | [70] |
3i41 | β-toxin | [71] |
2kam | δ-toxin | [72] |
1t2p, 1t2w | SrtA | [73] |
1ng5 | SrtB | [74] |
4lfd | SrtB | [75] |
4xs0 | IsdH-Hb | [76] |
5vmm | IsdB-Hb | [77] |
6tb2 | IsdH-Hb-Hp | [78] |
2ite, 2itf | IsdA | [79] |
2o6p | IsdC | [80] |
2q8q | IsdE | [81] |
1xbw | IsdG | [82] |
3lgn | IsdI | [83] |
System | Gene Cluster | Regulation | Strain | Deletion | Gene Contribution to Virulence in Vivo | Mouse Model of Infection | Evaluated District of Infection | Reference |
---|---|---|---|---|---|---|---|---|
Heme acquisition | ||||||||
Sortases | srtA | Constitutive | Newman | ΔsrtA | Yes | C57BL/6, Swiss-Webster (intravenous) | Kidney | [183] |
isdC-FsrtBisdG | Fur | Newman | ΔsrtA | Yes | NMRI (intra-articular) | Joints, kidney, blood | [184] | |
Newman, USA300 | ΔsrtA | Yes | BALB/c (intravenous) | Kidney | [150] | |||
Newman D2C | ΔsrtA | Yes | BALB/c (mammary injection) | Mammary glands | [185] | |||
Newman | ΔsrtA, ΔsrtA-srtB | Yes | CD-1 (intraperitoneal), | Systemic, joints, | [186] | |||
NMRI (intravenous), C3H/HeJ (bladder), Sprague-Dawley rats (intravenous) | kidney, heart | |||||||
Newman | ΔsrtA, ΔsrtA-srtB | Yes | NMRI (intravenous) | Joints, kidney | [187] | |||
Newman | ΔsrtB | Mild | Swiss-Webster (intravenous) | Kidney | [142] | |||
Newman | ΔsrtB | Mild | NMRI (intravenous) | Joints, kidney | [187] | |||
Newman | ΔsrtB | Mild | CD-1 (intraperitoneal), NMRI (intravenous), C3H/HeJ (bladder), Sprague-Dawley rats (intravenous) | Systemic, joints, kidney, heart | [186] | |||
Isd | isdA | Fur | Newman | ΔisdBH, ΔhtsA-isdE | No | BALB/c (intranasal) | Lung | [188] |
isdB | Fur | Newman | ΔhtsA-isdE | Yes | BALB/c (retro-orbital) | Lung, heart, kidney | [188] | |
isdC-FsrtBisdG | Fur | Newman | ΔisdB, ΔisdA | Yes | BALB/c (intravenous) | Kidney | [150] | |
orfXisdI | Fur | Newman | ΔisdC | Mild | BALB/c (intravenous) | Kidney | [150] | |
isdH | Fur | Newman | ΔisdH | No | BALB/c (intravenous) | Kidney | [150] | |
Newman | ΔisdB | Yes | C57BL/6J (retro-orbital) | Heart | [149] | |||
Newman | ΔisdB | No | C57BL/6J (retro-orbital) | Liver | [149] | |||
Newman | ΔisdA, ΔisdB, ΔisdC | Yes | BALB/c (retro-orbital) | Kidney | [151] | |||
Newman | ΔisdH | No | BALB/c (retro-orbital) | Kidney | [151] | |||
Newman | ΔisdG, ΔisdI, | Yes | BALB/c (retro-orbital) | Heart | [159] | |||
Newman | ΔisdG-I | No | BALB/c (retro-orbital) | Kidney | [159] | |||
Newman | ΔisdI | Yes | BALB/c (retro-orbital) | Kidney | [159] | |||
Newman | ΔisdG, ΔisdG-I | No | BALB/c (retro-orbital) | Liver | [159] | |||
Newman | ΔisdG, ΔisdI, | Mild | BALB/c (retro-orbital) | Kidney, spleen | [56] | |||
Newman | ΔisdG-I | Yes | BALB/c (retro-orbital) | Kidney, spleen | [56] | |||
8325-4 | ΔisdH | Yes | NMRI (intravenous) | Blood | [165] | |||
ΔisdB, ΔisdB-isdH | ||||||||
ΔisdH | ||||||||
Hss | hssRS | Constitutive, activated by heme | Newman | ΔhssR | Mutation increase virulence | BALB/c (retro-orbital) | Liver | [175] |
Newman | ΔhssR | No | BALB/c (retro-orbital) | Spleen, kidney | [175] | |||
Hrt | hrtAB | HssRS | Newman | ΔhrtA | Mutation increase virulence | BALB/c (retro-orbital) | Liver | [175] |
Newman | ΔhrtA | No | BALB/c (retro-orbital) | Spleen, kidney | [175] | |||
Endogenous siderophores | ||||||||
Staphyloferrin A | sfaABC | Fur | Newman | Δsfa | Yes | BALB/c (subcutaneous) | Skin | [88] |
sfaD | Fur | Newman | Δsfa-sbn | Yes | BALB/c (subcutaneous) | Skin | [88] | |
htsABC | Fur | |||||||
MW2 | ΔsfaA | Yes | Swiss-Webster (intravenous) | Kidney | [89] | |||
Newman | ΔhtsA-isdE | No | BALB/c (intranasal) | Lung | [188] | |||
Newman | ΔhtsA-isdE | Yes | BALB/c (retro-orbital) | Lung, heart, kidney | [188] | |||
Newman | ΔhtsB, ΔhtsC | Yes | BALB/c (intravenous) | Kidney, liver | [53] | |||
Staphyloferrin B | sbnA-I | Fur, SbnI | Newman | ΔsbnE | Yes | Swiss-Webster (intravenous) | Kidney | [90] |
sirABC | Fur | Newman | Δsbn | No | BALB/c (subcutaneous) | Skin | [99] | |
MW2 | ΔsbnD | Yes | Swiss-Webster (intravenous) | Kidney | [89] | |||
Newman | ΔsbnG | No | BALB/c (intravenous) | Heart, kidney, liver | [87] | |||
Newman | ΔsbnG-citZ | Yes | BALB/c (intravenous) | Heart, kidney, liver | [87] | |||
Newman | Δsfa-sbn, Δhts-sir, Δsfa-sbn-sst, | Yes | BALB/c (intravenous) | Heart, kidney, liver | [109] | |||
Δhts-sir-sst | ||||||||
Xenosiderophores | ||||||||
Hydroxamate | fhuBGC | Fur | Newman | ΔfhuD2 | Yes | CD1 (intravenous) | Kidney, blood | [110] |
fhuD1 | Fur | Newman | ΔfhuBGC | Yes | Swiss-Webster (intravenous) | Kidney | [189] | |
fhuD2 | Fur | |||||||
Catecholate | sstABCD | Fur | Newman | Δsst | Yes | BALB/c (intravenous) | Heart | [109] |
Inorganic iron acquisition | ||||||||
Fep | tatAC | Constitutive | RN1HG | ΔtatAC, Δtat-fep | Yes | BALB/c (intravenous) | Kidney | [170] |
fepABC | Fur |
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Marchetti, M.; De Bei, O.; Bettati, S.; Campanini, B.; Kovachka, S.; Gianquinto, E.; Spyrakis, F.; Ronda, L. Iron Metabolism at the Interface between Host and Pathogen: From Nutritional Immunity to Antibacterial Development. Int. J. Mol. Sci. 2020, 21, 2145. https://doi.org/10.3390/ijms21062145
Marchetti M, De Bei O, Bettati S, Campanini B, Kovachka S, Gianquinto E, Spyrakis F, Ronda L. Iron Metabolism at the Interface between Host and Pathogen: From Nutritional Immunity to Antibacterial Development. International Journal of Molecular Sciences. 2020; 21(6):2145. https://doi.org/10.3390/ijms21062145
Chicago/Turabian StyleMarchetti, Marialaura, Omar De Bei, Stefano Bettati, Barbara Campanini, Sandra Kovachka, Eleonora Gianquinto, Francesca Spyrakis, and Luca Ronda. 2020. "Iron Metabolism at the Interface between Host and Pathogen: From Nutritional Immunity to Antibacterial Development" International Journal of Molecular Sciences 21, no. 6: 2145. https://doi.org/10.3390/ijms21062145
APA StyleMarchetti, M., De Bei, O., Bettati, S., Campanini, B., Kovachka, S., Gianquinto, E., Spyrakis, F., & Ronda, L. (2020). Iron Metabolism at the Interface between Host and Pathogen: From Nutritional Immunity to Antibacterial Development. International Journal of Molecular Sciences, 21(6), 2145. https://doi.org/10.3390/ijms21062145