Abdelaziz MA. Recent Updates on The Pharmaceutical Applications of Siderophores

Mostafa A Abdelaziz

Review Article

Austin Pharmacol Pharm. 2024; 8(1): 1031.

Recent Updates on The Pharmaceutical Applications of Siderophores

Mostafa A Abdelaziz*

Department of Chemistry, The College of Wooster, 943 College Mall, Wooster, Ohio 44691, USA

*Corresponding author: Mostafa A. Abdelaziz Department of Chemistry, The College of Wooster, 943 College Mall, Wooster, Ohio 44691, USA. Tel: (234) 571-8377 Email: mabdelaziz@wooster.edu

Received: June 27, 2024 Accepted: July 12, 2024 Published: July 19, 2024

Abstract

Siderophores are low molecular weight (200-2000D) metal-chelating agents that can form complexes with iron and other essential elements. Siderophores are classified into three main classes: hydroxamate, phenolate and catecholate, and carboxylate. Natural and artificial siderophores have been widely used in a wide variety of environmental and medical applications. Siderophores have been utilized as antimicrobial agents or delivery carriers for antibiotics in the treatment of gram-negative resistant bacterial infections. They are also used as anticancer agents, antimalarial agents, and biosensors.

Keywords: Anti-microbial; Anti-cancer; Anti-malarial; Siderophores; Vaccines

Introduction

Iron plays a crucial role in biochemical processes of all microorganisms, plants, and animals. Although, iron is abundant in the earth’s crust, it sometimes has limited bioavailability in aerobic environments [1]. As a result, the living microorganisms and plants have developed strategies to absorb iron from the surrounding environment, such as soil and marine water. One of those strategies is biosynthesis of siderophores [2]. Siderophores are metal-chelating agents with masses ranging between 200 and 2000D that form complexes with iron and other essential elements, such as Mn, Co and Ni from the environment and render them bioavailable for microbial cells [2,3].

Siderophores are classified into three main classes: hydroxamates, catecholates and phenolates, and carboxylates, based on their chemical structures [4,5]. Hydroxamate siderophores have N-hydroxyamide (hydroxamate) functional group (-C(=O)-N(OH)-R), such as shizokinen, rhizobactin, as shown in Figure 1. Agrobactin, aminochelin and protochelin are examples of catecholate-based siderophores that are shown in Figure 2 [6].

Figure 1: Examples of hydroxamate siderophores with encircled hydroxamate functional group.

    
    
    Figure 1: Examples of hydroxamate siderophores with encircled hydroxamate functional group.

Figure 2: Examples of catecholate siderophores with encircled catecholate functional group.

    
    
    Figure 2: Examples of catecholate siderophores with encircled catecholate functional group.

Rhizoferrin is an example of carboxylate-type siderophore, which is produced by the fungus Rhizopus microspores. The structure of rhizoferrin is shown in Figure 3 [7,8]. Some siderophores are of mixed type, such as rhizobactin that has both hydroxamate and carboxylate functional groups (Figure 1).

Figure 3: Structure of rhizoferrin, an example of carboxylate-type siderophores.

    
    
    Figure 3: Structure of rhizoferrin, an example of carboxylate-type siderophores.

Microbial and plant siderophores, in addition to structurally related synthesized siderophores have been widely employed in many applications, including agriculture and medicine. In this review, we will discuss the medical applications of siderophores, such as anti-microbial therapy, chemotherapy, biosensors and vaccines [9].

Medical Applications of Siderophores

Siderophores as Antimicrobial Agents

Multi-drug bacterial resistance is one of the most challenging health issues that results in an urgent need for development of new antibiotics. Siderophores have attracted much attention as an alternative to overcome bacterial resistance. For example, Cefiderocol is a cephalosporin antibiotic-catecholate siderophore conjugate that displays a significant antimicrobial activity against cephalosporin-resistant Enterobacteriaceae (Figure 4) [10].

Figure 4: Structure of cefiderocol.

    
    
    Figure 4: Structure of cefiderocol.

One of the main factors that contributes to antibiotic resistance in gram-negative bacteria is inability of antibiotics to diffuse through the outer bacterial cell membrane [11]. Interestingly, siderophores have been utilized as carriers to deliver antibiotics through the outer bacterial membrane via iron-uptake pathways [12,13]. This strategy to overcome bacterial resistance is called “Trojan Horse” strategy [11]. For example, Peukert et al. reported the conjugation of daptomycin antibiotic to tetrapodal 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic amide (DOTAM) siderophore (Figure 5). It was observed that daptomycin-DOTAM conjugate has an enhanced uptake and significant antimicrobial effect against multidrug-resistant Acinetobacter baumannii [14].

Figure 5: Structure of daptomycin-DOTAM conjugate.

    
    
    Figure 5: Structure of daptomycin-DOTAM conjugate.

Siderophores as Anticancer Agents

Iron plays a crucial role in the growth of tumor tissues. Consequently, the ability of siderophores to scavenge iron from cellular environment has been harnessed to inhibit the proliferation of cancer cells, and tumor growth [15]. It was reported that fungal hydroxamate siderophores produced by Aspergillus spp. exhibit a significant does-dependent inhibition effect on the growth and proliferation of hepatocellular carcinoma cell line HepG2 [16]. Enterobactin, a bacterial catecholate siderophore shown in Figure 6 was also reported to exhibit a significant cytotoxic effect on monocyte-related tumor cell lines [17].