-
Nature Reviews. Microbiology Mar 2020Iron is an essential trace element for most organisms. A common way for bacteria to acquire this nutrient is through the secretion of siderophores, which are secondary... (Review)
Review
Iron is an essential trace element for most organisms. A common way for bacteria to acquire this nutrient is through the secretion of siderophores, which are secondary metabolites that scavenge iron from environmental stocks and deliver it to cells via specific receptors. While there has been tremendous interest in understanding the molecular basis of siderophore synthesis, uptake and regulation, questions about the ecological and evolutionary consequences of siderophore secretion have only recently received increasing attention. In this Review, we outline how eco-evolutionary questions can complement the mechanistic perspective and help to obtain a more integrated view of siderophores. In particular, we explain how secreted diffusible siderophores can affect other community members, leading to cooperative, exploitative and competitive interactions between individuals. These social interactions in turn can spur co-evolutionary arms races between strains and species, lead to ecological dependencies between them and potentially contribute to the formation of stable communities. In brief, this Review shows that siderophores are much more than just iron carriers: they are important mediators of interactions between members of microbial assemblies and the eukaryotic hosts they inhabit.
Topics: Bacteria; Biological Evolution; Iron; Microbial Interactions; Selection, Genetic; Siderophores
PubMed: 31748738
DOI: 10.1038/s41579-019-0284-4 -
Clinical Infectious Diseases : An... Nov 2019The emergence of antimicrobial resistance is a significant public health issue worldwide, particularly for healthcare-associated infections caused by... (Review)
Review
The emergence of antimicrobial resistance is a significant public health issue worldwide, particularly for healthcare-associated infections caused by carbapenem-resistant gram-negative pathogens. Cefiderocol is a novel siderophore cephalosporin targeting gram-negative bacteria, including strains with carbapenem resistance. The structural characteristics of cefiderocol show similarity to both ceftazidime and cefepime, which enable cefiderocol to withstand hydrolysis by β-lactamases. The unique chemical component is the addition of a catechol moiety on the C-3 side chain, which chelates iron and mimics naturally occurring siderophore molecules. Following the chelation of iron, cefiderocol is actively transported across the outer membrane of the bacterial cell to the periplasmic space via specialized iron transporter channels. Furthermore, cefiderocol has demonstrated structural stability against hydrolysis by both serine- and metallo-β-lactamases, including clinically relevant carbapenemases such as Klebsiella pneumoniae carbapenemase, oxacillin carbapenemase-48, and New Delhi metallo-β-lactamase. Cefiderocol has demonstrated promising in vitro antibacterial and bactericidal activity, which correlates with its in vivo efficacy in several animal models. This article reviews the discovery and chemistry of cefiderocol, as well as some of the key microbiological and in vivo findings on cefiderocol from recently conducted investigations.
Topics: Animals; Anti-Bacterial Agents; Cephalosporins; Drug Resistance, Bacterial; Gram-Negative Bacteria; History, 20th Century; Humans; Microbial Sensitivity Tests; Models, Molecular; Siderophores; Cefiderocol
PubMed: 31724047
DOI: 10.1093/cid/ciz826 -
Biomolecules May 2021Salicylic acid (SA) is an active secondary metabolite that occurs in bacteria, fungi, and plants. SA and its derivatives (collectively called salicylates) are... (Review)
Review
Salicylic acid (SA) is an active secondary metabolite that occurs in bacteria, fungi, and plants. SA and its derivatives (collectively called salicylates) are synthesized from chorismate (derived from shikimate pathway). SA is considered an important phytohormone that regulates various aspects of plant growth, environmental stress, and defense responses against pathogens. Besides plants, a large number of bacterial species, such as , , , , , , , and , have been reported to synthesize salicylates through the NRPS/PKS biosynthetic gene clusters. This bacterial salicylate production is often linked to the biosynthesis of small ferric-ion-chelating molecules, salicyl-derived siderophores (known as catecholate) under iron-limited conditions. Although bacteria possess entirely different biosynthetic pathways from plants, they share one common biosynthetic enzyme, isochorismate synthase, which converts chorismate to isochorismate, a common precursor for synthesizing SA. Additionally, SA in plants and bacteria can undergo several modifications to carry out their specific functions. In this review, we will systematically focus on the plant and bacterial salicylate biosynthesis and its metabolism.
Topics: Bacteria; Biosynthetic Pathways; Plant Growth Regulators; Plants; Salicylic Acid; Siderophores
PubMed: 34065121
DOI: 10.3390/biom11050705 -
Microbiological Research Sep 2021Iron is an essential element for all microorganisms. Siderophores are low-weight, high-affinity iron chelating molecules produced in response to iron deficiency by... (Review)
Review
Iron is an essential element for all microorganisms. Siderophores are low-weight, high-affinity iron chelating molecules produced in response to iron deficiency by Gram-positive and Gram-negative bacteria which also known as essential virulence factors of bacteria. Several studies have indicated that defective production and/or function of these molecules as well as iron acquisition systems in pathogens are associated with a reduction in pathogenicity of bacteria. Because of their potential role in various biological pathways, siderophores have been received special attention as secondary metabolites. Siderophores can detect iron levels in a variety of environments with a biosensor function. In medicine, siderophores are used to deliver antibiotics (Trojan horse strategy) to resistant bacteria and to treat diseases such as cancer and malaria. In this review, we discuss the iron acquisition pathways in Gram-positive and -negative bacteria, importance of siderophore production in pathogenesis of bacteria, classification of siderophores, and main applications of siderophores in medicine and industry.
Topics: Anti-Bacterial Agents; Biological Transport; Biosensing Techniques; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Industrial Microbiology; Iron; Iron Chelating Agents; Siderophores
PubMed: 34098495
DOI: 10.1016/j.micres.2021.126790 -
Chemical Reviews Jan 2019The highly contagious disease tuberculosis (TB) is caused by the bacterium Mycobacterium tuberculosis (Mtb), which has been evolving drug resistance at an alarming rate.... (Review)
Review
The highly contagious disease tuberculosis (TB) is caused by the bacterium Mycobacterium tuberculosis (Mtb), which has been evolving drug resistance at an alarming rate. Like all human pathogens, Mtb requires iron for growth and virulence. Consequently, Mtb iron transport is an emerging drug target. However, the development of anti-TB drugs aimed at these metabolic pathways has been restricted by the dearth of information on Mtb iron acquisition. In this Review, we describe the multiple strategies utilized by Mtb to acquire ferric iron and heme iron. Mtb iron uptake is a complex process, requiring biosynthesis and subsequent export of Mtb siderophores, followed by ferric iron scavenging and ferric-siderophore import into Mtb. Additionally, Mtb possesses two possible heme uptake pathways and an Mtb-specific mechanism of heme degradation that yields iron and novel heme-degradation products. We conclude with perspectives for potential therapeutics that could directly target Mtb heme and iron uptake machineries. We also highlight how hijacking Mtb heme and iron acquisition pathways for drug import may facilitate drug transport through the notoriously impregnable Mtb cell wall.
Topics: Bacterial Proteins; Biological Transport; Heme; Heme Oxygenase (Decyclizing); Humans; Iron; Mycobacterium tuberculosis; Siderophores; Tuberculosis; Virulence
PubMed: 30474981
DOI: 10.1021/acs.chemrev.8b00285 -
Free Radical Biology & Medicine Apr 2017Iron is an essential micronutrient for most life forms including the majority of resident bacteria of the microbiota and their mammalian hosts. Bacteria have evolved... (Review)
Review
Iron is an essential micronutrient for most life forms including the majority of resident bacteria of the microbiota and their mammalian hosts. Bacteria have evolved numerous mechanisms to competitively acquire iron within host environments, such as the secretion of small molecules known as siderophores that can solubilize iron for bacterial use. However, siderophore biosynthesis and acquisition is not a capability equally harbored by all resident bacteria. Moreover, the structural diversity of siderophores creates variability in the susceptibility to host mechanisms that serve to counteract siderophore-mediated iron acquisition and limit bacterial growth. As a result, the differential capabilities to acquire iron among members of a complex microbial community carry important implications for the growth and function of resident bacteria. Siderophores can also directly influence host function by modulating cellular iron homeostasis, further providing a mechanism by which resident bacteria may influence their local environment at the host-microbial interface. This review will explore the putative mechanisms by which siderophore production by resident bacteria in the intestines may influence microbial community dynamics and host-bacterial interactions with important implications for pathogen- and microbiota-driven diseases including infection, inflammatory bowel diseases and colorectal cancer.
Topics: Animals; Gastrointestinal Microbiome; Gastrointestinal Tract; Host-Pathogen Interactions; Humans; Intestinal Mucosa; Iron; Microbial Interactions; Siderophores
PubMed: 27780750
DOI: 10.1016/j.freeradbiomed.2016.10.489 -
Applied and Environmental Microbiology Mar 2022Pantoea ananatis is an emerging plant pathogen that causes disease in economically important crops such as rice, corn, onion, melon, and pineapple, and it also infects...
Negatively Regulated Aerobactin and Desferrioxamine E by Fur in Pantoea ananatis Are Required for Full Siderophore Production and Antibacterial Activity, but Not for Virulence.
Pantoea ananatis is an emerging plant pathogen that causes disease in economically important crops such as rice, corn, onion, melon, and pineapple, and it also infects humans and insects. In this study, we identified biosynthetic gene clusters of aerobactin and desferrioxamine E (DFO-E) siderophores by using the complete genome of PA13 isolated from rice sheath rot. PA13 exhibited the strongest antibacterial activity against Erwinia amylovora and Yersinia enterocolitica (). Mutants of aerobactin or DFO-E maintained antibacterial activity against E. amylovora and Y. enterocolitica, as well as in a siderophore activity assay. However, double aerobactin and DFO-E gene deletion mutants completely lost siderophore and antibacterial activity. These results reveal that both siderophore biosynthetic gene clusters are essential for siderophore production and antibacterial activity in PA13. A ferric uptake regulator protein (Fur) mutant exhibited a significant increase in siderophore production, and a Fur-overexpressing strain completely lost antibacterial activity. Expression of the , and genes was significantly increased in the Δ mutant background, and expression of these genes returned to wild-type levels after compensation. These results indicate that Fur negatively regulates aerobactin and DFO-E siderophores. However, siderophore production was not required for virulence in plants, but it appears to be involved in the microbial ecology surrounding the plant environment. This study is the first to report the regulation and functional characteristics of siderophore biosynthetic genes in . Pantoea ananatis is a bacterium that causes diseases in several economically important crops, as well as in insects and humans. This bacterium has been studied extensively as a potentially dangerous pathogen due to its saprophytic ability. Recently, the types, biosynthetic gene clusters, and origin of the siderophores in the genus were determined by using genome comparative analyses. However, few genetic studies have investigated the characteristics and functions of siderophores in . The results of this study revealed that the production of aerobactin and desferrioxamine E in the rice pathogen PA13 is negatively regulated by Fur and that these siderophores are essential for antibacterial activity against Erwinia amylovora and Yersinia enterocolitica (). However, siderophore production was not required for virulence in plants, but it appears to be involved in the microbial ecology surrounding the plant environment.
Topics: Anti-Bacterial Agents; Humans; Hydroxamic Acids; Lactams; Pantoea; Siderophores; Virulence
PubMed: 35108090
DOI: 10.1128/aem.02405-21 -
Marine Drugs May 2019Siderophores are low-molecular-weight metal chelators that function in microbial iron uptake. As iron limits primary productivity in many environments, siderophores are... (Review)
Review
Siderophores are low-molecular-weight metal chelators that function in microbial iron uptake. As iron limits primary productivity in many environments, siderophores are of great ecological importance. Additionally, their metal binding properties have attracted interest for uses in medicine and bioremediation. Here, we review the current state of knowledge concerning the siderophores produced by cyanobacteria. We give an overview of all cyanobacterial species with known siderophore production, finding siderophores produced in all but the most basal clades, and in a wide variety of environments. We explore what is known about the structure, biosynthesis, and cycling of the cyanobacterial siderophores that have been characterized: Synechobactin, schizokinen and anachelin. We also highlight alternative siderophore functionality and technological potential, finding allelopathic effects on competing phytoplankton and likely roles in limiting heavy-metal toxicity. Methodological improvements in siderophore characterization and detection are briefly described. Since most known cyanobacterial siderophores have not been structurally characterized, the application of mass spectrometry techniques will likely reveal a breadth of variation within these important molecules.
Topics: Cyanobacteria; Hydroxamic Acids; Iron; Iron Chelating Agents; Quinolinium Compounds; Siderophores
PubMed: 31083354
DOI: 10.3390/md17050281 -
Biomolecular Concepts Sep 2017Different aspects of bacterial and fungal siderophore biotechnological applications will be discussed. Areas of application presented include, but are not limited to... (Review)
Review
Different aspects of bacterial and fungal siderophore biotechnological applications will be discussed. Areas of application presented include, but are not limited to agriculture, medicine, pharmacology, bioremediation, biodegradation and food industry. In agriculture-related applications, siderophores could be employed to enhance plant growth due to their uptake by rhizobia. Siderophores hindered the presence of plant pathogens in biocontrol strategies. Bioremediation studies on siderophores discuss mostly the mobilization of heavy metals and radionuclides; the emulsifying effects of siderophore-producing microorganisms in oil-contaminated environments are also presented. The different applications found in literature based in medicine and pharmacological approaches range from iron overload to drug delivery systems and, more recently, vaccines. Additional research should be done in siderophore production and their metabolic relevance to have a deeper understanding for future biotechnological advances.
Topics: Agriculture; Biodegradation, Environmental; Biological Control Agents; Biotechnology; Drug Delivery Systems; Iron; Nanotechnology; Plant Development; Siderophores
PubMed: 28889118
DOI: 10.1515/bmc-2017-0016 -
Trends in Biochemical Sciences May 2018The menaquinone, siderophore, and tryptophan (MST) enzymes transform chorismate to generate precursor molecules for the biosynthetic pathways defined in their name.... (Review)
Review
The menaquinone, siderophore, and tryptophan (MST) enzymes transform chorismate to generate precursor molecules for the biosynthetic pathways defined in their name. Kinetic data, both steady-state and transient-state, and X-ray crystal structures indicate that these enzymes are highly conserved both in mechanism and in structure. Because these enzymes are found in pathogens but not in humans, there is considerable interest in these enzymes as drug design targets. While great progress has been made in defining enzyme structure and mechanism, inhibitor design has lagged behind. This review provides a detailed description of the evidence that begins to unravel the mystery of how the MST enzymes work, and how that information has been used in inhibitor design.
Topics: Humans; Kinetics; Lyases; Models, Molecular; Siderophores; Tryptophan; Vitamin K 2
PubMed: 29573882
DOI: 10.1016/j.tibs.2018.02.011