From a different perspective, attempts have been made to inhibit iron, which is essential for the growth and proliferation of pathogenic microorganisms, as a strategy to increase antimicrobial activity (Schwarz et al. 2019; Scott et al. 2020). Specifically, the strategy is to use iron chelators in combination with antibacterial and antifungal agents. We hypothesize that the impregnation of catheters with antimicrobial agents and iron chelators would increase their antimicrobial and anti-biofilm activity and inhibit microbial colony and biofilm formation, resulting in reduced CRI incidence and longer catheter use, as shown in Fig. 2. The surface and lumen of the catheter are impregnated with antimicrobial and iron-chelating agents, which are assumed to inhibit bacterial and fungal colony and biofilm formation by exerting antimicrobial and iron-chelating activities on the bacteria and fungi that attach to the surface.
Support For The Hypothesis
Antimicrobial activity of iron chelators
Because of its redox potential, iron is involved in many biochemical reactions. Iron is an essential element for all living organisms, including bacterial pathogens (Dev and Babitt 2017). It also plays an important role as a cofactor in various intracellular pathways, such as DNA synthesis and repair, electron transfer, oxygen transport, and immune response (Scott et al. 2020). Iron levels in the human body are strictly regulated to protect against the toxic effects of free iron, which catalyzes the generation of reactive oxygen species (ROS), and the utilization of iron by invading microorganisms (Dixon and Stockwell 2014). Through nutritional immunity, humans inhibit microbial growth by starving microorganisms of the metal ions they need (Hood and Skaar 2012; Palmer and Skaar 2016). Bacteria and fungi bind iron using high-affinity chelating compounds, called siderophores, as a strategy to acquire iron. Numerous types of siderophores have been reported. Siderophores are categorized into three main structural familiesࣧcarboxylates, catecholates, and hydroxamatesࣧwith the catecholate siderophore, enterobactin, showing the highest affinity for iron, even higher than that for the host iron-binding protein, transferrin (Ellermann and Arthur 2017). Iron chelators may be useful in the treatment of infectious diseases by limiting the availability of iron, thereby inhibiting the production of ROS, and by inhibiting microbial growth due to nutrient restriction (Lehmann et al. 2021; Paterson et al. 2022).
To date, the combinations of vancomycin and deferasirox against methicillin-resistant Staphylococcus aureus (Luo et al. 2014), doxycycline, and the iron chelator CP762 against Pseudomonas aeruginosa (Faure et al. 2021), and the triple combination of doxycycline, deferasirox, and thiostrepton (an antibiotic against gram-positive bacteria) against P. aeruginosa and Acinetobacter baumannii (Chan et al. 2020) have shown promising effects both in vitro and in animal models. For fungi, animal model experiments of combination therapy with liposomal amphotericin B (L-AMB), micafungin, and deferasirox against Aspergillus and Mucor (Ibrahim et al. 2011), animal experiments of combination therapy with L-AMB and deferasirox against Aspergillus fumigatus (Ibrahim et al. 2010), and in vitro experiments of combination therapy with AMB and deferoxamine against Cryptococcus spp. (Chayakulkeeree et al. 2020) have indicated that these combinations are useful. Despite promising experimental data for the combination of deferasirox and L-AMB for mucormycosis (Ibrahim et al. 2011, 2007; Schwarz et al. 2019), unexpectedly, a higher mortality rate at 90 days was seen with the combination than with L-AMB alone in a randomized controlled trial (Spellberg et al. 2012).
Nevertheless, iron-chelation therapy still has potential for clinical applications. Different types of iron-chelating agents have been shown to have different antimicrobial activities. Of those tested, a water-soluble agent containing iron-selective copolymers (denying iron to bacterial infections; DIBI) was the most effective (Fe Pharmaceuticals; Lehmann et al. 2021). Recent studies have reported the promising finding that a combination of DIBI and antimicrobials may overcome drug-resistant bacteria and fungi. DIBI in combination with ciprofloxacin has been shown to be successful in treating ciprofloxacin-resistant A. baumannii-infected mice (Parquet et al. 2019). Moreover, the combination of DIBI and fluconazole was found to inhibit the growth of fluconazole-resistant Candida albicans in an in vitro study (Savage et al. 2018). These findings suggest that the appropriate selection of a type of iron chelator and its combination with an antimicrobial agent may be useful for dealing with a broad spectrum of infectious pathogens, and may overcome antibiotic resistance mechanisms.
Anti-biofilm Activity Of Iron Chelators
One notable problem related to CVC implantation is biofilm formation. Here, we further explain the relationship between iron chelators and biofilm formation. It has already been mentioned that iron is essential for bacterial and fungal growth and proliferation, but it is also required for biofilm formation (Coraça-Huber et al. 2018; Firoz et al. 2021; Nazik et al. 2015). Microorganisms produce biofilms that protect them against antimicrobials, making them drug resistant (Brauner et al. 2016; Høiby et al. 2010; Singh et al. 2010; Thi et al. 2020). Hence, methods are needed to inhibit the formation of biofilms and attack the microorganisms that have formed within them. The following are examples of attempts that have been made to develop such methods. Iron-chelation therapy has been tested in P. aeruginosa to explore adjunctive therapy for chronic P. aeruginosa infection, primarily in patients with cystic fibrosis. Deferiprone, a synthetic iron chelator, has been shown to inhibit biofilm formation (Houshmandyar et al. 2021). Furthermore, the combination of iron chelators and antimicrobial agents has shown enhanced biofilm inhibitory activity; examples include combination therapy with the iron (VI) chelator N,N'-bis (2-hydroxybenzyl) ethylenediamine-N,N'-diacetic acid and colistin in an in vitro experiment (Mettrick et al. 2020), and with the iron chelators deferoxamine or deferasirox and tobramycin (Moreau-Marquis et al. 2009). Lactoferrin, an iron-binding glycoprotein that is a component of human secretions, also has iron-chelating activity (Singh 2004), and ALX-109, an investigational agent containing lactoferrin and hypothiocyanite (a bactericidal agent), has shown activity against P. aeruginosa biofilms in combination with tobramycin and aztreonam (Moreau-Marquis et al. 2015). Deferasirox has shown biofilm inhibitory effects on the periodontal bacterium Prevotella intermedia (Moon et al. 2013), and lactoferrin treatment has significantly reduced interleukin (IL)-1, IL-6, IL-8, and tumor necrosis factor α production by gingival fibroblasts infected with P. intermedia. Moreover, an observational clinical trial of patients with periodontitis showed that treatment with lactoferrin reduced cytokines such as IL-6, edema, bleeding, pocket depth and gingival and plaque indices in the crevicular fluid and improved clinical adhesion levels (Berlutti et al. 2011). Several studies conducted on Staphylococcus spp. 1,2,3,4,6-Penta-O-galloyl-β-D-glucopyranose, a plant-derived ingredient with iron-chelating properties commonly used in Chinese medicine, have shown biofilm inhibitory effects on S. aureus (Lin et al. 2012). The combination of deferiprone and the heme analog gallium protoporphyrin in combination with gentamicin or ciprofloxacin increased the biofilm inhibitory effects in an S. aureus colony biofilm model (Richter et al. 2017). Additionally, for coagulase-negative staphylococci, deferiprone showed enhanced antibacterial activity in combination with clindamycin, gentamicin, or vancomycin by disrupting biofilms (Coraça-Huber et al. 2018). Regarding fungi, deferiprone inhibited biofilm formation by A. fumigatus, whereas deferoxamine had the opposite effect, and promoted biofilm formation. The result of the promotion of biofilm formation by deferoxamine may be due to A. fumigatus acquiring more iron chelator complexes through a siderophore-like mechanism (Nazik et al. 2015). Thus, depending on the combination of the type of microorganism and iron chelator, the microorganism has a tolerance mechanism and takes advantage of iron starvation. However, iron chelators have a different point of action than do antibacterial and antifungal agents, and thus, may carry less risk of inducing drug resistance in microorganisms. This is a major advantage of combining drugs with different mechanisms of action.