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Antibiotic resistance is a global health concern and a current threat to modern medicine and society. New strategies for antibiotic drug design and delivery offer a glimmer of hope in a currently limited pipeline of new antibiotics. One strategy involves conjugating iron-chelating microbial siderophores to an antibiotic or antimicrobial agent to enhance uptake and antibacterial potency. Cefiderocol (S-649266) is a promising cephalosporin–catechol conjugate currently in phase III clinical trials that utilizes iron-mediated active transport and demonstrates enhanced potency against multi-drug resistant (MDR) Gram-negative pathogens. Such molecules demonstrate that siderophore–antibiotic conjugates could be important future medicines to add to our antibiotic arsenal. This review is written in the context of the chemical design of siderophore–antibiotic conjugates focusing on the differing siderophore, linker, and antibiotic components that make up conjugates. We selected chemically distinct siderophore–antibiotic conjugates as exemplary conjugates, rather than multiple analogues, to highlight findings to date. The review should offer a general guide to the uninitiated in the molecular design of siderophore–antibiotic conjugates.

Cefiderocol is a novel siderophore cephalosporin with potent activity against gram-negative bacteria, including multidrug-resistant strains. This Phase I study was conducted to assess the tolerability of single-ascending doses of cefiderocol (part 1) and the effect of cefiderocol on cardiac repolarization, assessed using the electrocardiographic corrected QT interval (QTcF) and other ECG parameters (part 2), in healthy adult subjects. Part 1 was a randomized, double-blind, placebo-controlled, single-ascending dose study in healthy adult male and female subjects. Part 2 was a 4-period crossover study in which subjects received a single 2-g dose of cefiderocol (therapeutic dose), a single 4-g dose of cefiderocol (supratherapeutic dose), or saline (placebo), each infused over 3 hours, and a single oral 400-mg dose of moxifloxacin. In each treatment period, continuous cardiac monitoring was used to assess the effects of cefiderocol on ECG parameters. The QT interval corrected using the Fridericia formula (QTcF) was the primary ECG parameter; the time-matched placebo- and baseline-adjusted (dd)-QTcF interval was the primary end point. The plasma pharmacokinetic properties of cefiderocol were calculated on the basis of concentration–time profiles in all evaluable subjects. All point estimates for the ddQTcF interval were <5 ms and the upper bound of the 90% CIs were <10 ms at each timepoint after the initiation of the cefiderocol 3-hour infusion. Concentration-effect modeling showed a slightly negative slope and predicted modestly negative values of the ddQTcF interval at the Cmax of cefiderocol. Both doses of cefiderocol were well tolerated. All adverse events were mild in severity, with no deaths or serious adverse events reported. Overall, therapeutic and supratherapeutic doses of cefiderocol had no apparent clinically significant effect on the QTcF.

Iron is an essential nutrient for bacterial growth, replication, and metabolism. Humans store iron bound to various proteins such as hemoglobin, haptoglobin, transferrin, ferritin, and lactoferrin, limiting the availability of free iron for pathogenic bacteria. However, bacteria have developed various mechanisms to sequester or scavenge iron from the host environment. Iron can be taken up by means of active transport systems that consist of bacterial small molecule siderophores, outer membrane siderophore receptors, the TonB-ExbBD energy-transducing proteins coupling the outer and the inner membranes, and inner membrane transporters. Some bacteria also express outer membrane receptors for iron-binding proteins of the host and extract iron directly from these for uptake. Ultimately, iron is acquired and transported into the bacterial cytoplasm. The siderophores are small molecules produced and released by nearly all bacterial species and are classified according to the chemical nature of their iron-chelating group (ie, catechol, hydroxamate, α-hydroxyl-carboxylate, or mixed types). Siderophore-conjugated antibiotics that exploit such iron-transport systems are under development for the treatment of infections caused by gram-negative bacteria. Despite demonstrating high in vitro potency against pathogenic multidrug-resistant bacteria, further development of several candidates had stopped due to apparent adaptive resistance during exposure, lack of consistent in vivo efficacy, or emergence of side effects in the host. However, cefiderocol, with an optimized structure, has advanced and has been investigated in phase 1 to 3 clinical trials. This article discusses the mechanisms implicated in iron uptake and the challenges associated with the design and utilization of siderophore-mimicking antibiotics.

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.

Shewanella are bacteria widespread in marine and brackish water environments and emergent opportunistic pathogens. Their environmental versatility depends on the ability to produce numerous iron-rich proteins, mainly multiheme c -type cytochromes. Although iron plays a vital role in the versatility of Shewanella species, very few studies exist regarding the strategies by which these bacteria scavenge iron from the environment. Siderophore-mediated iron transport is a commonly employed strategy for iron acquisition, and it was identified among Shewanella spp. over two decades ago. Shewanella species produce hydroxamate-type siderophores and iron removal from these compounds can occur in the cytoplasm via Fe(III)–siderophore reduction mediated by siderophore-interacting proteins (SIPs). The genome of Shewanella putrefaciens DSM 9451 isolated from an infected child contains representatives of the two different families of SIPs: the flavin-containing siderophore reductase ( Sb SIP) and the iron–sulfur cluster-containing ferric–siderophore reductase ( Sb FSR). Here, we report their expression, purification, and further biochemical characterization of Sb SIP. The structural and functional characterization of Sb SIP and comparison with the homologous SIP from Shewanella frigidimarina ( Sf SIP) revealed similarities between these proteins including a common binding pocket for NADH, NADPH, and siderophore substrates plus a pronounced redox-Bohr effect that ensures coupled transfer of electrons and protons in the physiological pH range. These mechanistic aspects open the door for further investigations on developing drugs that interfere with the iron metabolism of these bacteria and thereby prevent their spread. Graphical abstract

Late wilt disease, caused by Cephalosporium maydis in maize plant, is one of the main economical diseases in Egypt. Therefore, to cope with this problem, we investigated the potentiality of plant growth promoting rhizobacteria in controlling this disease. Six strains (Bacillus subtilis, B. circulance, B. coagulanse, B. licheniformis, Pseudomonas fluroscence and P. koreensis) were screened for siderophore production, and using dual plate culture method and greenhouse experiment, antagonistic activity against C. maydis was studied. Using two superior strains, single and dual inoculation treatments in maize were applied in field experiment during the 2018 and 2019 seasons. Results indicated that B. subtilis and P. koreensis strains had shown the most qualitative and quantitative assays for siderophore production and antagonistic activities. In greenhouse, the most effective treatments on the pre- and post-emergence damping off as well as growth promotion of maize were T3 treatment (inoculated with B. subtilis), and T8 treatment (inoculated with P. koreensis). In field experiment, T5 treatment (inoculated with a mixture of B. subtilis and P. koreensis) showed significant increases in catalase (CAT), peroxidase (POX) and polyphenol oxidase (PPO) activities, as well as total chlorophyll and carotenoids than control treatments during the two growing seasons. In the same way, the highest effect in reducing infection and increasing the thickness of the sclerenchymatous sheath layer surrounding the vascular bundles in maize stem was observed and these results were a reflection of the increase in yield and yield parameters.

Two Streptomyces spp. were isolated from open ocean waters of the Gulf of Mannar. Of the two isolates, one was identified as Streptomyces coelicolor through conventional and molecular approaches, and it was found to produce a siderophore. Characterization revealed the siderophore to be of trihydroxamate type with hexadentate iron-binding capacity. FTIR analysis indicated the presence of aromatic rings with C–O and C = C stretching, while 1 H and 13 C NMR together with mass spectrometry confirmed the hydroxamate nature and identified the siderophore as ferrioxamine. A narrow shift in λ max indicate the photoreactive nature of the siderophore on exposure to sunlight. The cell-free supernatant of S. coelicolor and the purified siderophore dose-dependently inhibited the growth of microbial pathogens. Quorum quenching activity was confirmed using the indicator strain Chromobacterium violaceum . Both the cell-free supernatant and siderophore were found to inhibit biofilm formation and induce reactive oxygen species (ROS) generation in pathogens. The siderophore also suppressed the proliferation of the breast cancer cell line (MCF-7) by disturbing iron homeostasis. Optimization of International Streptomyces Project (ISP2) medium constituents using two-level factorial design and response surface methodology (RSM) enabled cost-effective siderophore production. In addition to iron, the siderophore exhibited binding affinity for other heavy metals including zinc, cobalt, cadmium, lead, and magnesium.

Background The ability of plant growth-promoting rhizobacteria (PGPR) to alleviate iron deficiency-induced chlorosis in plants has been widely reported, but the role of siderophores in the re-greening process has rarely been investigated. In this study, the Priestia megaterium ZS-3 (ZS-3) siderophore was first characterized, and a 100-fold concentration of the crude extract of the siderophore was extracted by solid-phase extraction and used to inoculate Arabidopsis thaliana to investigate whether the ZS-3 siderophore could alleviate plant iron deficiency-induced chlorosis in the presence of an insoluble iron source and to determine how it promoted plant growth. Results The results indicated that -Fe + Fe 2 O 3 (Fe 2 O 3 ) treatment induced a decrease in plant growth and iron nutritional status compared with those in the 1/2 MS (one-half-strength Murashige and Skoog medium). Expression levels of representative genes for chlorophyll synthesis, CHLM and CHLG , increased by 85.41% and 77.05% compared to Fe 2 O 3 treatment; the IRT1 and FRO 2 in Fe 2 O 3 inoculated with the ZS-3 siderophore (T2 treatment) were upregulated by 88.1% and 87.20%, respectively. These results indicate that the ZS-3 siderophore upregulates the expressions of chlorophyll genes to increases photosynthesis and helps plants increase the transcription of iron and the activity of ferric-chelate reductase. Compared with the Fe 2 O 3 treatment, the T2 group increased the soluble protein and chlorophyll contents by 2.64- and 3.47-fold, and improved the activities of ferric-chelate reductase and peroxidase (POD) by 3.69- and 2.9-fold, respectively, indicating that the ZS-3 siderophore maintained normal plant growth under Fe 2 O 3 stress by increasing the activity of antioxidant enzymes. Conclusions This study revealed that the ZS-3 siderophore Ferrioxamine E [M + Fe-2 H] enhances plant iron uptake and transport activity at the transcriptional level, confirming the important role of the ZS-3 siderophore in plant iron deficiency status, and the results suggest that the ZS-3 siderophore helps plants acquire iron, alleviates plant chlorosis and promotes plant growth through mechanism I of plant iron acquisition. In this study, we closely linked the structural characterization and quantification of siderophores with Fe deficiency-induced chlorosis to elucidate the promotional mechanism of siderophores in Fe-deficient environments.

Siderophores are low-molecular-weight secondary metabolites that function as iron chelators. Under iron-deficiency conditions, they are produced by a wide variety of microbes, allowing them to increase their iron uptake. The primary function of these compounds is the environmental iron scavenging and its transport into the cytosol. Iron is then reduced to its ferrous form to operate as an enzymatic cofactor for various functions, including respiration, nitrogen fixation, photosynthesis, methanogenesis, and amino acid synthesis. Depending on their functional group, siderophores are classified into hydroxamate, catecholate, phenolate, carboxylate, and mixed types. They have achieved great importance in recent years due to their medical applications as antimicrobial, antimalarial, or anticancer drugs, vaccines, and drug-delivery agents. This review integrates current advances in specific healthcare applications of microbial siderophores, delineating new opportunities and challenges as viable therapies to fight against diseases that represent crucial public health problems in the medical field.Key points• Siderophores are low-molecular-weight secondary metabolites functioning as iron chelators.• The siderophore’s properties offer viable options to face diverse clinical problems.• Siderophores are alternatives for the enhancement of antibiotic activities.

Staphylococcus aureus is a versatile opportunistic human pathogen. Infection by this bacterium requires uptake of iron from the human host, but iron is highly restricted in this environment. Staphylococcus aureus iron sufficiency is achieved primarily through uptake of heme and high-affinity iron chelators, known as siderophores. Two siderophores (staphyloferrins) are produced and secreted by S. aureus into the extracellular environment to capture iron. Staphylococcus aureus expresses specific uptake systems for staphyloferrins and more general uptake systems for siderophores produced by other microorganisms. The S. aureus heme uptake system uses highly-specific cell surface receptors to extract heme from hemoglobin and hemoglobin-haptoglobin complexes for transport into the cytoplasm where it is degraded to liberate iron. Initially thought to be independent systems, recent findings indicate that these iron uptake pathways intersect. IruO is a reductase that releases iron from heme and some ferric-siderophores. Moreover, multifunctional SbnI produces a precursor for staphyloferrin B biosynthesis, and also binds heme to regulate expression of the staphyloferrin B biosynthesis pathway. Intersection of the S. aureus iron uptake pathways is hypothesized to be important for rapid adaptation to available iron sources. Components of the heme and siderophore uptake systems are currently being targeted in the development of therapeutics against S. aureus.