Siderophores (microbial iron chelators) and siderophore-drug conjugates (new methods for microbially selective drug delivery)

Although iron is one of the most abundant elements, its pivotal role in the evolution of life on earth depended on the development of effective methods for its assimilation. Ionic forms of iron, especially iron(III), its most common state, are very insoluble under physiological conditions. To circumvent the solubility problem, many microbes, plants and even higher organisms synthesize and utilize very specific low molecular weight iron chelators called siderophores ("iron bearers"). When grown under iron deficient conditions, many microbes will synthesize and excrete siderophores in excess of their own dry cell weight to sequester and solubilize iron. This extreme focus on the need for iron is reflected by its requirement for the proper function of the enzymes that facilitate electron transport, oxygen transport and other life-sustaining processes. In fact, competition for iron between a host and bacteria is one of the most important factors determining the course of a bacterial infection. Different organisms utilize structurally varied siderophores to also competitively bind iron and gain selective growth advantages.

Siderophores and analogs have tremendous therapeutic potential, yet few practical applications of siderophores have been realized. One potentially powerful application is to use the iron transport abilities of siderophores to carry drugs into cells by preparation of conjugates between siderophores and antimicrobial agents. Because microbes recognize and utilize only certain siderophores, such conjugates were anticipated to have selective antimicrobial activity. Testing this "Trojan horse" concept required the ability to synthesize siderophores, and analogs, as well as the ability to attach suitable drugs. Approaches to the syntheses of the structurally complex siderophores was limited by the need for efficient syntheses of the corresponding iron chelating components themselves. Dr. Miller's group has developed very general and efficient syntheses of all the functional components of the known siderophores. Most recently, they developed methodology for the direct biomimetic oxidation of amine side chains of ornithine and lysine to hydroxylamine derivatives needed for iron chelation. The resulting N-hydroxyamino acids are the most important and commonly used components of natural iron chelators. Previous syntheses required many chemical steps and/or resolution of racemic material. Miller's laboratory completed the first total syntheses of a number of siderophores, including aerobactin, arthrobactin, schizokinen, a mycobactin, foroxymithine, all of the components of pseudobactin and several analogs. Recent efforts have been directed towards the syntheses and study of siderophore-antimicrobial agent conjugates in a program designed to develop iron transport-mediated drug delivery agents such as 1-3. Conjugate 1a and 1b contain a siderophore component bound to a potent new class of beta-lactam antibiotics called the carbacephalosporins. Conjugate 1c incorporates an erythromycin analog; whereas, conjugate 1d incorporates a siderophore and a novel antifungal agent related to the neoenactins, first synthesized in Dr. Miller's laboratory. Conjugates containing the same drugs, but different siderophore components (such as 2a-e) target different microbes. Detailed biological studies indicate that the concept of microbial iron transport (siderophore)-mediated drug delivery is remarkably effective! Microbes that recognize the siderophore component as an iron delivery agent assimilate the conjugate, and in effect, commit suicide since the attached drug is lethal to them. Indications are that this alternate mode of drug delivery may lead to the development of whole new classes of antimicrobial agents based on active transport of an essential nutrient and sideorphore conjugation may rejuvenate old drugs that relied on passive diffusion and to which resistance has developed. Interestingly, preliminary studies of some of the synthetic siderophore analogs, such as forms of 3, indicate that they have considerable potential as non-toxic, organ selective magnetic resonance imaging (MRI) contrast agents.