Polyglycerol-Based Macromolecular Iron Chelator Adjuvants for Antibiotics To Treat Drug-Resistant Bacteria

Abstract

Iron is an essential micronutrient for life. Its redox activity is a key component in a plethora of vital enzymatic reactions that take place in processes such as drug metabolism, DNA synthesis, steroid synthesis, gene regulation, and cellular respiration (oxygen transport and the electron transport chain). Bacteria are highly dependent on iron for their survival and growth and have specific mechanisms to acquire iron. Limiting the availability of iron to bacteria, thereby preventing their growth, provides new opportunities to treat infection in the era of the persistent rise of antibiotic-resistant bacteria. In this work, we have developed macromolecular iron chelators, conjugates of a high-affinity iron chelator (HBEDS) with polyglycerol, in an attempt to sequester iron uptake by bacteria to limit their growth in order to enhance antibiotic activity. The new macromolecular chelators are successful in slowing the growth of Staphylococcus aureus and worked as an efficient bacteriostatic against S. aureus. Further, these cytocompatible macrochelators acted as effective adjuvants to prevent bacterial growth when used in conjunction with antibiotics. The adjuvant activity of the macrochelators depends on their molecular weight and the chelator density on these molecules. These selective macro iron­(III) chelators are highly efficient in growth inhibition and killing of methicillin-resistant S. aureus in conjunction with a low concentration of rifampicin.

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

“…Following a similar approach, Abbina and co-workers synthesized a series of very-high-molecular-weight Fe 3+ chelators, by conjugating the hexadentate chelator, N,N- bis(2-hydroxybenzyl)ethylenediamine- N,N -diacetic acid (HBED), with high-molecular-weight polyglycerol (HPG) [ 37 ]. Exploiting the characteristics of HPG (high water solubility, biocompatibility, and numerous functional end-moieties), they obtained different 100–200 kDa HPG-HBED conjugates, bearing a high number of chelating groups, ranging from 25 to 244.…”

Role of Iron in the Molecular Pathogenesis of Diseases and Therapeutic Opportunities

“…This macromolecular chelator showed bacterial growth inhibition in studies on S. aureus and MRSA as both an adjuvant with rifampicin and as a standalone treatment. This conjugation approach enhanced the solubility of HBEDS and also helped reduce its toxicity …”

“…260,266,270,271 The accumulation of iron in different areas, including neurons, microglia, and astrocytes of brain, causes oxidative damage and mitochondrial injury. 272,273 Further, the accumulated excess iron can accelerate and or initiate protein misfolding, alterations in protein structures, and 229,249 secondary iron overload, stroke in vitro, preclinical intravenous polyglycerol-DFO 218,220,224 secondary iron overload preclinical intravenous degradable ketal polymer-DFO 218 secondary iron overload preclinical intravenous polyglycerol-HBED 250 bacterial infection in vitro NA starch or hydroxyethyl starch or dextran-DFO 230,251,252 secondary iron overload and cancer preclinical/clinical intravenous hyaluronic acid-DFO 231 wound healing preclinical intraoperative implantation alginate-DFO 225 secondary iron overload in vitro NA polyallylamines-DFO 208,222 secondary iron overload preclinical oral polyrotaxanes-DFO 234,253 secondary iron overload preclinical intravenous nanogels (acrylate-PEG copolymer and DFO) 226,227,233 iron overload disorders preclinical intravenous BSA-non heme 223 Parkinson's disease preclinical intraperitoneal poly(ethylene glycol)-poly(aspartic acid) (PEG-PAsp) block copolymers-DFO 254 iron chelation cancer therapy preclinical intravenous poly(catechol)-PEG-DFO 255 intracerebral hemorrhage preclinical NA nanoparticle formulations deferasirox film-coated tablet (Jadenu) 256 iron overload disorders approved oral liposome encapsulated deferoxamine 257 iron overload disorders preclinical intravenous PEG−PLGA and DFO 242 iron overload disorders and Parkinson's disease preclinical intravenous and intraperitoneal PLA and PLGA and thiosemicarbazones 258 anticancer act...…”

“…This conjugation approach enhanced the solubility of HBEDS and also helped reduce its toxicity. 250 7. IRON DEFICIENCY: PATHOPHYSIOLOGY So far, we have focused on iron metabolism and the adverse effects due to excess iron in the body and available methods to derisk these conditions.…”

Iron Metabolism and Ferroptosis in Epilepsy

“…Iron is an essential trace element for the growth and development of humans. Iron compounds are also involved in many redox reactions: oxygen transport, cellular oxidative respiratory chain, tricarboxylic acid cycle, and DNA biosynthesis (Thirupathi and Chang, 2019;Abbina et al, 2020). However, in the nervous system, iron is closely related to the formation of myelin, the metabolism of catecholamine neurotransmitters, and is also involved in intellectual development and neurodegenerative diseases (Thirupathi and Chang, 2019).…”