Present and Future of Siderophore-Based Therapeutic and Diagnostic Approaches in Infectious Diseases

Abstract

Iron is an essential micronutrient required for the growth of almost all aerobic organisms; the iron uptake pathway in bacteria therefore represents a possible target for novel antimicrobials, including hybrids between antimicrobials and siderophores. Siderophores are low molecular weight iron chelators that bind to iron and are actively transported inside the cell through specific binding protein complexes. These binding protein complexes are present both in Gram negative bacteria, in their outer and inner membrane, and in Gram positive bacteria in their cytoplasmic membrane. Most bacteria have the ability to produce siderophores in order to survive in environments with limited concentrations of free iron, however some bacteria synthetize natural siderophore-antibiotic conjugates that exploit the siderophore-iron uptake pathway to deliver antibiotics into competing bacterial cells and gain a competitive advantage. This approach has been referred to as a Trojan Horse Strategy. To overcome the increasing global problem of antibiotic resistance in Gram negative bacteria, which often have reduced outer membrane permeability, siderophore-antibiotic hybrid conjugates have been synthetized in vitro. Cefiderocol is the first siderophore-antibiotic conjugate that progressed to late stage clinical development so far. In studies on murine models the iron-siderophore uptake pathway has been also exploited for diagnostic imaging of infectious diseases, in which labelled siderophores have been used as specific probes. The aim of this review is to describe the research progress in the field of siderophore-based therapeutic and diagnostic approaches in infectious diseases.

Hydroxamate siderophores: Natural occurrence, chemical synthesis, iron binding affinity and use as Trojan horses against pathogens

“…Hydroxamic acids have found many applications in medical and agricultural practices [109] and as probes [1,3]. Their medical use can be therapeutic or diagnostic [110].…”

“…All bacteria susceptible to the microbicidal activity of these hydroxamate sideromycins were found to have the FhuA receptor in their membranes. These sideromycins function better under iron starvation conditions than under conditions of sufficiency [3]. Iron starvation can be achieved by using biostatic agents (strong chelators that bind iron tightly).…”

“…Although accounting for about 35% of Earth's mass [2], its bioavailability to microorganisms is limited. This is attributed to the fact that under anaerobic conditions, iron is present as Fe (III), which in aqueous media is either precipitated out (trapped) as insoluble hydroxides (Ksp = 10 -18 M) or is bound to host proteins such as transferrin, ferritin and lactoferrin leaving the free Fe (III) at concentrations as low as 1 x 10 -24 M [1,3].…”

Financial Market Prediction and Simulation Based on the FEPA Model

“…Before the efficient market hypothesis was put forward, there were many literatures on the predictability of securities prices. For example, Liang et al [13] found that the changes of securities prices and commodity prices in European and American markets were random; Nápoles et al [14] found that the stock price time series in the United States is random and cannot be distinguished from the series generated by a random number series; Tonziello et al [15] found that the characteristics of stock price behavior are similar to those of particles in fluid and accord with the characteristics of random walk. It is these empirical studies that found the unpredictability of market price that prompted economists to think about the reasons for the random walk of securities price and finally promoted the formation of efficient market hypothesis theory.…”

Total Synthesis of the Reported Structure of Cahuitamycin A

“…These results also impact organic chemists studying antibiotic natural products, especially those targeting bacterial virulence. Siderophore-mediated iron-acquisition as an antibiotic target has been a topic of broad interest 20 and has recently even resulted in an FDA approved drug (cefiderocol, brand name Fetrojaâ). 21 The SAR from the isolation report points to an asof-yet unidentified relationship between the activity of the cahuitamycins and their similarity to the siderophores of A. baumannii.…”