Siderophores: A Novel Approach to Fight Antimicrobial Resistance
The increasing bacterial resistance subsequent to antibiotic use has instigated the development of new and effective antimicrobial strategies. Bacterial iron uptake systems are novel therapeutic agents since iron is crucial for the growth and development of microorganisms as well as a main virulence factor during the establishment of an infection. The method commonly used for iron assimilation is based on the production of siderophores, which are low molecular weight iron chelators produced by bacteria, fungi, and plants to facilitate iron uptake and crucial for bacterial pathogenicity. Therefore, in recent year’s siderophore iron uptake, systems have received much attention as novel targets for antimicrobial approaches.
Here we review siderophores in the antimicrobial field. We first outline the problematic of bacterial resistance to available marketed antibacterial drugs and, consequently, the current needs to contrast with the emergence of bacterial resistance. After, we emphasize the critical role of iron for bacterial growth and development and how pathogens compete with the host for iron. The biosynthesis, regulation, and transport of siderophores are also discussed. Lastly, we review work done with siderophores in the antimicrobial field. Such work has generally been done using three essential approaches: siderophore-mediated drug delivery, inhibition of siderophores biosynthesis, and iron starvation via competitive chelation.
KeywordsAntimicrobial resistance Bacterial infections Biofilm Drug delivery Iron Siderophores Trojan Horse approach
This work was supported by projects: POCI-01-0145-FEDER-030219; POCI-01-0145-FEDER-007274; POCI-01-0145-FEDER-029777; POCI-01-0145-FEDER-006939 – Laboratory for Process Engineering, Environment, Biotechnology and Energy (LEPABE) – funded by Fundo Europeu de Desenvolvimento Regional (FEDER) funds through COMPETE2020 – Programa Operacional Competitividade e Internacionalização (POCI); by national funds through Fundação para a Ciência e a Tecnologia (FCT) and the post-doc grant awarded to Anabela Borges (SFRH/BPD/98684/2013); and project NORTE-01-0145-FEDER-000005 – LEPABE-2-ECO-INNOVATION, funded by Fundo Europeu de Desenvolvimento Regional (FEDER) through COMPETE2020 – Programa Operacional Competitividade e Internacionalização (POCI) and Programa Operacional Regional do Norte (NORTE2020).
- Beasley FC, Marolda CL, Cheung J, Buac S, Heinrichs DE (2011) Staphylococcus aureus transporters Hts, Sir, and Sst capture iron liberated from human transferrin by Staphyloferrin A, Staphyloferrin B, and catecholamine stress hormones, respectively, and contribute to virulence. Infect Immun 79:2345–2355. https://doi.org/10.1128/IAI.00117-11 CrossRefGoogle Scholar
- Cai S, Qiao X, Feng L, Shi N, Wang H, Yang H, Guo Z, Wang M, Chen Y, Wang Y (2018) Python cathelicidin CATHPb1 protects against multidrug-resistant staphylococcal infections by antimicrobial-immunomodulatory duality. J Med Chem 61:2075–2086. https://doi.org/10.1021/acs.jmedchem.8b00036 CrossRefGoogle Scholar
- Dale SE, Doherty-Kirby A, Lajoie G, Heinrichs DE (2004) Role of siderophore biosynthesis in virulence of Staphylococcus aureus: identification and characterization of genes involved in production of a siderophore. Infect Immun 72:29–37. https://doi.org/10.1128/IAI.72.1.29-37.2004 CrossRefGoogle Scholar
- Dave BP, Anshuman K, Hajela P (2006) Siderophores of halophilic archaea and their chemical characterization. Indian J Exp Biol 44:340–344Google Scholar
- Ellermann M, Arthur JC (2017) Siderophore-mediated iron acquisition and modulation of host-bacterial interactions. Free Radic Biol Med 105:68–78. https://doi.org/10.1016/j.freeradbiomed.2016.10.489 CrossRefGoogle Scholar
- Finking R, Marahiel MA (2004) Biosynthesis of nonribosomal peptides1. Annu Rev Microbiol 58:453–488. https://doi.org/10.1146/annurev.micro.58.030603.123615 CrossRefGoogle Scholar
- Glick R, Gilmour C, Tremblay J, Satanower S, Avidan O, Deziel E, Greenberg EP, Poole K, Banin E (2010) Increase in rhamnolipid synthesis under iron-limiting conditions influences surface motility and biofilm formation in Pseudomonas aeruginosa. J Bacteriol 192:2973–2980. https://doi.org/10.1128/JB.01601-09 CrossRefGoogle Scholar
- Holden VI, Lenio S, Kuick R, Ramakrishnan SK, Shah YM, Bachman MA (2014) Bacterial siderophores that evade or overwhelm lipocalin 2 induce hypoxia inducible factor 1α and proinflammatory cytokine secretion in cultured respiratory epithelial cells. Infect Immun 82:3826–3836. https://doi.org/10.1128/IAI.01849-14 CrossRefGoogle Scholar
- Ivanova A, Ivanova K, Hoyo J, Heinze T, Sanchez-Gomez S, Tzanov T (2018) Layer-by-layer decorated nanoparticles with uunable antibacterial and antibiofilm properties against both Gram-Positive and Gram-Negative bacteria. ACS Appl Mater Interfaces 10:3314–3323. https://doi.org/10.1021/acsami.7b16508 CrossRefGoogle Scholar
- Murray J, Muruko T, Gill CI, Kearney MP, Farren D, Scott MG, McMullan G, Ternan NG (2017) Evaluation of bactericidal and anti-biofilm properties of a novel surface-active organosilane biocide against healthcare associated pathogens and Pseudomonas aeruginosa biolfilm. PLoS One 12:e0182624. https://doi.org/10.1371/journal.pone.0182624 CrossRefGoogle Scholar
- Noinaj N, Guillier M, Barnard TJ, Buchanan SK (2010) TonB-dependent transporters: regulation, structure, and function. Annu Rev Microbiol 64:43–60. https://doi.org/10.1146/annurev.micro.112408.134247 CrossRefGoogle Scholar
- Raad I, Chatzinikolaou I, Chaiban G, Hanna H, Hachem R, Dvorak T, Cook G, Costerton W (2003) In vitro and ex vivo activities of minocycline and EDTA against microorganisms embedded in biofilm on catheter surfaces. Antimicrob Agents Chemother 47:3580–3585. https://doi.org/10.1128/AAC.47.11.3580-3585.2003 CrossRefGoogle Scholar
- Russo TA, Page MG, Beanan JM, Olson R, Hujer AM, Hujer KM, Jacobs M, Bajaksouzian S, Endimiani A, Bonomo RA (2011) In vivo and in vitro activity of the siderophore monosulfactam BAL30072 against Acinetobacter baumannii. J Antimicrob Chemother 66:867–873. https://doi.org/10.1093/jac/dkr013 CrossRefGoogle Scholar
- Singh S, Kalia NP, Joshi P, Kumar A, Sharma PR, Kumar A, Bharate SB, Khan IA (2017) Boeravinone B, A novel dual inhibitor of NorA bacterial efflux pump of Staphylococcus aureus and human P-glycoprotein, reduces the biofilm formation and intracellular invasion of bacteria. Front Microbiol 8:1868. https://doi.org/10.3389/fmicb.2017.01868 CrossRefGoogle Scholar
- Wandersman C, Delepelaire P (2004) Bacterial iron sources: from siderophores to hemophores. Annu Rev Microbiol 58:611–647. https://doi.org/10.1146/annurev.micro.58.030603.123811 CrossRefGoogle Scholar