| Abstract |
Infectious diseases account for millions of deaths worldwide annually, while bacterial resistance to antibiotic therapy is a major world health problem that is responsible for more than 700,000 of those deaths. Bacterial infection and the evolution of multi-drug resistance (MDR), therefore, represent an increasingly formidable challenge in the developed and developing world with a colossal economic, societal and environmental impact, posing a significant clinical challenge in patients with cystic fibrosis, burns and skin wounds. Increasing resistance to currently available antibiotics has been mirrored by decreases in the design/development of new antibiotic entities as the pharmaceutical industry has replaced antibiotic development with drug development in diseases with a better risk-reward ratio. These trends have led to the existence of organisms that are susceptible to just 1 or 2 antibiotics, and in some cases, none at all. To overcome these problems, clinicians are increasingly employing (as drugs of last resort) older antibiotics, such as colistin, which, despite the high incidence of toxicity and significant long-term complications, are effective. Use of colistin to fight infection is limited, as it is known to be toxic to the kidneys, despite the fact that it has been found to be effective against MDR bacteria. This project will test a new method of drug delivery for the safe administration of antibiotics, currently rendered unusable due to toxicity issues. These so-called "polymer therapeutics" are capable of reducing the side effects of conventional drugs by shielding them in a polymer coat, but once they reach the site of disease, they can be triggered to release the drug by the body's own proteins. This approach enables drugs to specifically accumulate at sites of disease at a much higher concentration than normal, thus, patients require lower doses and less frequent dosing. This study will test a new nano-sized antibiotic system, called dextrin-colistin conjugates, in which the antibiotic, colistin, is chemically wrapped in a safe, water-soluble, naturally-occurring biodegradable polymer (dextrin). Having previously demonstrated improvements in drug shielding, retention of antimicrobial activity and drug distribution in the body, this project will test whether dextrin attachment can effectively reduce colistin's harmful effects on the kidneys. We predict that dextrin-colistin conjugates will cause less damage to the kidneys than the unmodified antibiotic or the clinical formulation of colistin, CMS, due to reduced exposure of kidney cells to colistin. This study will use several different approaches to test this hypothesis, including: 1. Measure the growth and survival of cells grown in the laboratory in the presence of different drug treatments. These studies will use cells originating from the kidney as well as skin cells, for comparison. 2. Quantify the amount of drug that enters inside kidney and skin cells grown in the laboratory. Here, a compound that lights up under fluorescent light will be chemically attached to the drugs to allow visualisation under a microscope or in a laser beam. 3. Assess how drugs spread around the body of healthy rats compared to those with a bacterial infection. Damage to kidneys will be measured visually and by testing blood samples for specific proteins that are released when the kidneys are injured. These experiments will test different doses of antibiotic drugs to identify the maximum dose tolerated by the animals. This dose will then be used to test the ability of the drug treatments to cure a lung infection. Ultimately, if this study is successful, not only will we have demonstrated the safety and efficacy of these new antibiotics, but there is great potential for the use of water-soluble natural polymers in a wide range of chronic human diseases of high public health impacts, including cystic fibrosis, spinal cord injury and diabetic foot ulcers. |