Iron Acquisition and Metabolism as a Promising Target for Antimicrobials (Bottlenecks and Opportunities): Where Do We Stand?

Abstract

The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) infections is one of the most crucial challenges currently faced by the scientific community. Developments in the fundamental understanding of their underlying mechanisms may open new perspectives in drug discovery. In this review, we conducted a systematic literature search in PubMed, Web of Science, and Scopus, to collect information on innovative strategies to hinder iron acquisition in bacteria. In detail, we discussed the most interesting targets from iron uptake and metabolism pathways, and examined the main chemical entities that exhibit anti-infective activities by interfering with their function. The mechanism of action of each drug candidate was also reviewed, together with its pharmacodynamic, pharmacokinetic, and toxicological properties. The comprehensive knowledge of such an impactful area of research will hopefully reflect in the discovery of newer antibiotics able to effectively tackle the antimicrobial resistance issue.

Moles of Molecules against Mycobacterium abscessus: A Review of Current Research

“…An emerging strategy to kill bacteria is targeting virulence factors. Indeed, inhibition of non-essential pathways involved in bacterial growth or disruption of the processes involved in the pathogenesis applies a low evolutive selection compared to targeting essential genes [127]. For instance, targeting the biosynthesis of mycobacterial siderophores, known as mycobactins and involved in host iron scavenging, is an exquisite strategy attracting different study groups of Mtb.…”

“…Iron Fe 3+ and gallium Ga 3+ have indeed similar features; indeed, gallium-based molecules have been successfully applied to fight other bacterial infections [132][133][134]. Gallium has the ability to disrupt the iron acquisition systems and to impair the function of heme-utilizing hemeproteins; hence, it perturbates multiple aspects of pathogens [127]. Gallium protoporphyrin (GaPP, Table 9), gallium mesoporphyrin (GaMP), and gallium nitrate (Ga(NO3)3) have been tested against Mab in a depleted-iron medium.…”

Identification of small molecules affecting the interaction between human hemoglobin and Staphylococcus aureus IsdB hemophore

“…Here we exploited an integrated in silico/in vitro approach to identify, for the first time, non-peptidic ligands able to interfere with the binding of Hb to IsdB, with the far-reaching aim of developing protein–protein interaction (PPI) inhibitors able to interfere with hemic iron acquisition by S. aureus 27 . Our approach consists of targeting free Hb, which is released from erythrocytes in the bloodstream by the action of bacterial hemolysins, with small molecules unable to cross the red blood cell membrane, and therefore without interfering with intracellular Hb.…”

Structural Study of a New MbtI-Inhibitor Complex: Towards an Optimized Model for Structure-Based Drug Discovery

“…In mammals, it is mainly bound in its oxidized form (Fe 3+ ) to iron-storage or transport proteins, due to its toxicity and low solubility [4,5]. As pathogenic microorganisms need this essential metal to ensure their survival and sustain their pathogenicity, most higher organisms, including humans, have evolved an innate defensive strategy based on the restriction of the amount of available extracellular iron [6][7][8][9]. Nevertheless, many pathogens, mainly bacteria and fungi, have developed efficient countermeasures to compensate for this effect [10][11][12].…”

“…Nevertheless, many pathogens, mainly bacteria and fungi, have developed efficient countermeasures to compensate for this effect [10][11][12]. In mycobacteria, one of the most important iron acquisition pathways relies on the production of siderophores [3,6,13]. These low-molecular-weight chelators, known as carboxymycobactins (cMBTs) and mycobactins (MBTs), share a common core but differ in their terminal portion, leading to different solubility and functional properties.…”