The Hydroxypyridinone Iron Chelator DIBI Reduces Bacterial Load and Inflammation in Experimental Lung Infection.

Iron plays a critical role in lung infections due to its function in the inflammatory immune response but also as an important factor for bacterial growth. Iron chelation represents a potential therapeutic approach to inhibit bacterial growth and pathologically increased pro-inflammatory mediator production. The present study was designed to investigate the impact of the iron chelator DIBI in murine lung infection induced by intratracheal (strain PA14) administration.

Iron Chelation as a Potential Therapeutic Approach in Acute Lung Injury.

Acute lung injury (ALI) has been challenging health care systems since before the COVID-19 pandemic due to its morbidity, mortality, and length of hospital stay. In view of the complex pathogenesis of ALI, effective strategies for its prevention and treatment are still lacking. A growing body of evidence suggests that iron dysregulation is a common characteristic in many subtypes of ALI.

Iron Withdrawal with DIBI, a Novel 3-Hydroxypyridin-4-One Chelator Iron-Binding Polymer, Attenuates Macrophage Inflammatory Responses.

Iron is an essential trace element for the inflammatory response to infection. In this study, we determined the effect of the recently developed iron-binding polymer DIBI on the synthesis of inflammatory mediators by RAW 264.7 macrophages and bone marrow-derived macrophages (BMDMs) in response to lipopolysaccharide (LPS) stimulation.

Dysregulated Iron Homeostasis as Common Disease Etiology and Promising Therapeutic Target.

Iron is irreplaceably required for animal and human cells as it provides the activity center for a wide variety of essential enzymes needed for energy production, nucleic acid synthesis, carbon metabolism and cellular defense. However, iron is toxic when present in excess and its uptake and storage must, therefore, be tightly regulated to avoid damage. A growing body of evidence indicates that iron dysregulation leading to excess quantities of free reactive iron is responsible for a wide range of otherwise discrete diseases.

Iron Chelator DIBI Suppresses Formation of Ciprofloxacin-Induced Antibiotic Resistance in .

Antibiotic resistance of bacterial pathogens results from their exposure to antibiotics and this has become a serious growing problem that limits effective use of antibiotics. Resistance can arise from mutations induced by antibiotic-mediated damage with these mutants possessing reduced target sensitivity. We have studied ciprofloxacin (CIP)-mediated killing of and the influence of the Reactive Oxygen Species (ROS) inactivator, thiourea and the iron chelator DIBI, on initial killing by CIP and their effects on survival and outgrowth upon prolonged exposure to CIP.

Anti-Inflammatory Effects of the Iron Chelator, DIBI, in Experimental Acute Lung Injury.

Iron plays a critical role in the immune response to inflammation and infection due to its role in the catalysis of reactive oxygen species (ROS) through the Haber-Weiss and Fenton reactions. However, ROS overproduction can be harmful and damage healthy cells. Therefore, iron chelation represents an innovative pharmacological approach to limit excess ROS formation and the related pro-inflammatory mediator cascades.

Antimicrobial Activity of the Iron-Chelator, DIBI, against Multidrug-Resistant Canine Methicillin-Susceptible : A Preliminary Study of Four Clinical Strains.

is an important opportunistic pathogen causing various infections in dogs. Furthermore, it is an emerging zoonotic agent and both multidrug-resistant methicillin-resistant (MRSP) as well as methicillin-susceptible (MSSP) strains represent an important therapeutic challenge to veterinary medicine and pose a potential threat to human health. We tested representative clinical strains from dogs suffering from otitis externa for their susceptibilities to a panel of 17 antimicrobials compared to DIBI.

Anti-inflammatory iron chelator, DIBI, reduces leukocyte-endothelial adhesion and clinical symptoms of LPS-induced interstitial cystitis in mice.

Background: Interstitial cystitis (IC) is a prevalent and debilitating chronic inflammatory disease of the urinary bladder. Currently there are no fully effective therapeutic agents available, in part due to the still obscure pathogenesis of IC. Lipopolysaccharide (LPS) also known as endotoxin from Gram negative bacteria elicits IC in mice and has formed the basis of model systems for investigation.

Iron-withdrawing anti-infectives for new host-directed therapies based on iron dependence, the Achilles' heel of antibiotic-resistant microbes.

The iron dependence of antibiotic-resistant microbes represents an Achilles' heel that can be exploited broadly. The growing global problem of antibiotic resistance of microbial pathogens wherein microbes become resistant to the very antibiotics used against them during infection is linked not only to our health uses but also to agribusiness practices and the changing environment. Here we review mechanisms of microbial iron acquisition and host iron withdrawal defense, and the influence of iron withdrawal on the antimicrobial activity of antibiotics.

Comparison of Treatment Effects of Different Iron Chelators in Experimental Models of Sepsis.

Growing evidence indicates that dysregulated iron metabolism with altered and excess iron availability in some body compartments plays a significant role in the course of infection and sepsis in humans. Given that all bacterial pathogens require iron for growth, that iron withdrawal is a normal component of innate host defenses and that bacterial pathogens have acquired increasing levels of antibiotic resistance, targeting infection and sepsis through use of appropriate iron chelators has potential to provide new therapeutics. We have directly compared the effects of three Food and Drug Administration (FDA)-approved chelators (deferoxamine-DFO; deferiprone-DFP; and deferasirox-DFX), as were developed for treating hematological iron overload conditions, to DIBI, a novel purpose-designed, anti-infective and anti-inflammatory water-soluble hydroxypyridinone containing iron-selective copolymers.

Enhanced Fe binding through cooperativity of 3-hydroxypyridin-4-one groups within a linear co-polymer: wrapping effect leading to superior antimicrobial activity.

To tackle the rise of antibiotic resistant pathogenic microbes, iron withdrawal agents have shown considerable promise as antibiotic alternatives due to the microbes' irreplaceable metabolic need for the essential element iron. DIBI is a water-soluble, linear co-polymer functionalized with 3-hydroxy-pyridin-4-one (HPO) chelators that selectively and strongly bind iron(III) in biological environments. Compared to HPO congeners, DIBI has over 1000 times higher antimicrobial activity against a broad-spectrum of Gram-(+) and Gram-(-) bacteria including highly antibiotic resistant clinical isolates.

The novel iron chelator, DIBI, attenuates inflammation and improves outcome in colon ascendens stent peritonitis-induced experimental sepsis.

Background: Sepsis is the result of a dysregulated host immune response to an infection. An ideal therapy would target both the underlying infection and the dysregulated immune response. DIBI, a novel iron-binding polymer, was specifically developed as an antimicrobial agent and has also demonstrated in vivo anti-inflammatory properties.

Iron Chelation in Murine Models of Systemic Inflammation Induced by Gram-Positive and Gram-Negative Toxins.

Iron is an essential element for various physiological processes, but its levels must remain tightly regulated to avoid cellular damage. Similarly, iron plays a dual role in systemic inflammation, such as with sepsis. Leukocytes utilize iron to produce reactive oxygen species (ROS) to kill bacteria, but pathologically increased iron-catalyzed ROS production in sepsis can lead to damage of host cells, multi-organ failure and death.

Iron Sequestrant DIBI, a Potential Alternative for Nares Decolonization of Methicillin-Resistant Staphylococcus aureus, Is Anti-infective and Inhibitory for Mupirocin-Resistant Isolates.

Methicillin-resistant (MRSA) opportunistic infections are a major health burden. Decolonization of hospitalized patients with mupirocin (MUP) has reduced the incidence of infection but has led to MUP resistance. DIBI is a developmental-stage anti-infective agent that sequesters bacterial iron and bolsters innate host iron-withdrawal defenses.

DIBI, a novel 3-hydroxypyridin-4-one chelator iron-binding polymer, inhibits breast cancer cell growth and functions as a chemosensitizer by promoting S-phase DNA damage.

Breast cancer is a leading cause of cancer-related death in women; however, chemotherapy of breast cancer is often hindered by dose-limiting toxicities, demonstrating the need for less toxic approaches to treatment. Since the rapid growth and metabolism of breast cancer cells results in an increased requirement for iron, withdrawal of bioavailable iron using highly selective iron chelators has been suggested to represent a new approach to breast cancer treatment. Here we show that the recently developed iron-binding polymer DIBI inhibited the growth of five different breast cancer cell lines (SK-BR3, MDA-MB-468, MDA-MB-231, MCF-7, and T47D).

Iron should be restricted in acute infection.

The trace element iron plays important roles in biological systems. Vital functions of both host organisms and pathogens require iron. During infection, the innate immune system reduces iron availability for invading organisms.

Potential Mechanisms of Mucin-Enhanced Acinetobacter baumannii Virulence in the Mouse Model of Intraperitoneal Infection.

Porcine mucin has been commonly used to enhance the infectivity of bacterial pathogens, including , in animal models, but the mechanisms for enhancement by mucin remain relatively unknown. In this study, using the mouse model of intraperitoneal (i.p.

Antibiotic-Resistant Is Susceptible to the Novel Iron-Sequestering Anti-infective DIBI and in Experimental Pneumonia in Mice.

is a major cause of nosocomial infections especially hospital-acquired pneumonia. This bacterium readily acquires antibiotic resistance traits and therefore, new treatment alternatives are urgently needed. The virulence of linked to iron acquisition suggests a potential for new anti-infectives that target its iron acquisition.

Iron Chelation as Novel Treatment for Interstitial Cystitis.

Interstitial cystitis (IC) is a highly prevalent debilitating disease, with its cardinal symptoms being severe pain, urinary urgency and frequency. The associated pain may eventually lead as a last resort to removal of the bladder. Though the initial trigger for IC remains largely unknown, we propose novel iron chelators as a possible new treatment for this disease.

Selective sensitivity of the gut microbiome to iron chelators in polybacterial abdominal sepsis.

Iron chelation has been proposed as a potential therapy for polybacterial abdominal sepsis. Treatment with iron chelation is known to be able to attenuate bacterial growth. It is hypothesized that the different types of bacteria will exhibit variations in their sensitivity to iron chelation based on differences in their iron metabolism.

Novel Iron-Chelator DIBI Inhibits Growth, Suppresses Experimental MRSA Infection in Mice and Enhances the Activities of Diverse Antibiotics .

DIBI, a purpose-designed hydroxypyridinone-containing iron-chelating antimicrobial polymer was studied for its anti-staphylococcal activities in comparison to deferiprone, the chemically related, small molecule hydroxypyridinone chelator. The sensitivities of 18 clinical isolates of from human, canine and bovine infections were determined. DIBI was strongly inhibitory to all isolates, displaying approximately 100-fold more inhibitory activity than deferiprone when compared on their molar iron-binding capacities.

DIBI, a 3-hydroxypyridin-4-one chelator iron-binding polymer with enhanced antimicrobial activity.

Depriving microorganisms of bioavailable iron is a promising strategy for new anti-infective agents. The new, highly water-soluble, low molecular weight co-polymer DIBI was developed to selectively bind iron(iii) ions as a tris chelate and acts as a standalone anti-infective. Minimum inhibitory concentration (MIC) studies show DIBI is effective against representative reference strains for Gram-positive and Gram-negative bacteria and , and the fungus .

Iron Restriction to Clinical Isolates of Candida albicans by the Novel Chelator DIBI Inhibits Growth and Increases Sensitivity to Azoles and in a Murine Model of Experimental Vaginitis.

is an important opportunistic pathogen causing various human infections that are often treated with azole antifungals. The U.S.