Antibiotic resistance – problems, challenges and circumvention
The potential of targeted siderophore – antibiotic conjugates in combating drug resistant bacterial infections
Over the past 100 years, life expectancy has increased by about 50%.Over half of that unprecedented change is due to what has been called the “Golden Era of Antibiotics”.However, bacterial resistance to antibiotics is now a major problem that affects nearly all areas of medicine, from treatment of what were commonly cured infections to concerns during lifesaving surgery.
Bacteria use multiple strategies to survive exposure to antibiotics, including acquisition or evolution of genes for antibiotic-modifying enzymes (i.e., β-lactamases), efflux pumps, alteration of drug target and decreased cell permeability. These are problems for all current antibiotics and, need to be addressed in the development of new antibiotics.
Thus, new efforts to circumvent resistance processes are desperately needed.Attempts include the search for new antibiotic scaffolds with new antibacterial targets or methods to extend utility of our current, albeit, limited set of antibiotics.One area of interest is to exploit essential bacterial iron assimilation processes as new targets or for active transport of bacteria, especially across the outer membrane of Gram-negative bacteria.
Bacteria need iron for growth and virulence.The concentration of iron in mammalian hosts is much too low to sustain bacteria. Under these extreme iron deficient events, bacteria produce small molecules called siderophores (Greek for “iron carrier”), which are low molecular weight, highly selective, iron binders.Once excreted, siderophores bind iron tightly to form iron complexes recognized by bacterial receptors that initiate uptake by the bacterial cells. This active iron pumping process is an exquisite example of growth regulation by molecular recognition that enables bacterial infections, even under astronomically low iron conditions. Several research groups have attached iron binding agents to antibiotics, especially penicillin-like drugs, but most have failed because their siderophore targeting did not closely resemble natural bacterial siderophores. Inspired by a few known natural examples, the groups at the University of Notre Dame and Hsiri Therapeutics, LLC, and others, have designed and prepared synthetic sideromycins (antibiotics attached to siderophores) with careful attention to mimic the structures of natural siderophores. This close mimicry of nature is the key advantage for molecular recognition – based active transport.Indeed, studies of targeted siderophore conjugates of beta-lactam antibiotics revealed that, as planned, these synthetic sideromycins have potent in vitro and in vivo activity against targeted Gram-negative bacteria, including strains of Acinetobacter baumannii, Pseudomonas aeruginosa, E. coli and other pathogens, whereas the base antibiotic components alone (penicillin, loracarbef and cephalosporins) had no in vivo efficacy.Tailor made sideromycin activity against extensive beta-lactamase producing bacteria is augmented by co-treatment with commercial beta-lactamase inhibitors.In order to further demonstrate the utility of carefully designed sideromycins, the Hsiri group also conjugated an Acinetobacter baumannii selective siderophore to daptomycin, an antibiotic that is valuable for treatment of Gram-positive bacterial infections.While daptomycin itself has no activity against Gram-negative bacteria, including Acinetobacter, the resulting conjugate displayed excellent in vitro activity against several multi-drug resistant strains with MIC levels of <0.125 µM to 3 µM and in vivo efficacy using a survival model in mice infected with A. baumannii.
Overall, these studies indicate that molecular recognition based siderophore mediated drug delivery has significant potential for combating drug resistant bacterial infections.