Iron Acquisition Systems of Gram-negative Bacterial Pathogens Define TonB-Dependent Pathways to Novel Antibiotics

Abstract

Iron is an indispensable metabolic cofactor in both pro-and eukaryotes, which engenders a natural competition for the metal between bacterial pathogens and their human or animal hosts. Bacteria secrete siderophores that extract Fe 3+ from tissues, fluids, cells, and proteins; the ligand gated porins of the Gram-negative bacterial outer membrane actively acquire the resulting ferric siderophores, as well as other iron-containing molecules like heme. Conversely, eukaryotic hosts combat bacterial iron scavenging by sequestering Fe 3+ in binding proteins and ferritin. The variety of iron uptake systems in Gram-negative bacterial pathogens illustrates a range of chemical and biochemical mechanisms that facilitate microbial pathogenesis. This document attempts to summarize and understand these processes, to guide discovery of immunological or chemical interventions that may thwart infectious disease.

Porin threading drives receptor disengagement and establishes active colicin transport through Escherichia coli OmpF

“…This impermeability problem is a major factor in multidrug resistance amongst Gram‐negative pathogens. One approach being developed to circumvent these issues is to conjugate complex antibiotics to siderophores (so‐called Trojan horse antibiotics) so that they can be actively transported through specific TBDTs, energised by the PMF‐linked Ton‐system (Klebba et al , 2021). Our data show that large, bulky, organic fluorophores that approach the size and complexity of vancomycin can be actively transported through the porins of E. coli by piggy‐backing on a colicin.…”

Rhizobiales -Specific RirA Represses a Naturally “Synthetic” Foreign Siderophore Gene Cluster To Maintain Sinorhizobium -Legume Mutualism

“…Abundant iron exists in the biosphere but mainly in the oxidized ferric (Fe 3+ ) form that is insoluble under neutral and basic pH conditions ( 1 ). To utilize the available ferric iron, many bacteria secrete siderophores to scavenge Fe 3+ by forming soluble ferric siderophore complexes, which can be then actively taken up via specific outer membrane receptors (Gram-negative bacteria) and various ABC transporters (both Gram-negative and Gram-positive bacteria) ( 2 , 3 ). Hundreds of known siderophores fall under four main chemical classes, catecholate, hydroxamate, carboxylate, and phenolate, which are distinguished from each other on the basis of moieties chelating ferric iron ( 2 ).…”

“…There are plenty of examples of uptake of ferric siderophore complexes as a public good by siderophore nonproducers and co-occurring cheating resistance mechanisms in siderophore producers such as secreting different siderophores ( 4 – 7 ). Notable variations in iron affinity of siderophores and condition-dependent stability of ferric siderophore complexes ( 3 , 8 ) make siderophores a competitive trait of bacteria ( 9 ). This, in turn, drives horizontal transfer of various siderophore biosynthesis and/or transport genes among bacteria ( 10 ); however, the regulatory integration process during or post-horizontal transfer is poorly understood.…”

Plasmon-Enhanced Antibacterial Activity of Chiral Gold Nanoparticles and In Vivo Therapeutic Effect

“…[ 1 , 2 , 3 ], which is the most concerning issue in public health [ 1 , 2 , 3 ]. E. coli , a Gram-negative, non-sporulating facultative anaerobe bacteria, is commonly found in the lower intestine and known as a harmless commensal of the gastrointestinal tract in warm-blooded animals [ 4 , 5 , 6 ]. However, E. coli can produce an enzyme called broad-spectrum β-lactamase that cause urinary tract infections.…”