Dr. Anne Duhme-Klair
University of York

Siderophore-linked Drugs as Novel Antimicrobial Agents

The health disparities that afflict ethnic and racial minorities, as well as other underserved populations, are not limited to one or two disease categories. They apply to a broad spectrum of disease including infectious diseases. The problem presented by infectious diseases is compounded by the rise of antibiotic resistance strains that in some cases defy treatment with most if not all antibiotics. Infant mortality is augmented by infectious diseases, specially those caused by resistant strains and mortality is also increased in patients that are more susceptible to them as consequence of the presence of another disease such as AIDS, cancer or diabetes.

The problem of bacterial resistance to antibiotics is now so severe that it has been described as a crisis by the World Health Organisation. It is therefore important to find novel ways of combating the development of resistance. As iron is a key growth factor for most pathogenic bacteria, their survival depends on the ability to acquire Fe(III) from the host. To remove the Fe(III) from the mammalian Fe-binding proteins, bacteria produce and secrete high-affinity iron chelators, so called siderophores. These siderophores scavenge the iron by forming extremely stable Fe(III)-complexes.

Our approach is to use a 'Trojan Horse' strategy. This approach involves attaching the antimicrobial agent to a siderophore with the desired effect being that the antibiotic is taken up along with the siderophore when the bacterium is sequestering iron. If the bacteria mutate to block the entry of the siderophore-linked antibiotic, they will suffer from iron starvation and hence die. In addition, it has recently been recognised that multidrug efflux pumps select and bind hydrophobic drugs within the lipid bilayer of the membrane, the utilisation of the Fe-uptake system to transport drugs into the cell could bypass efflux pumps. The aim of this project is to synthesise a selection of siderophore-linked drugs, to study their iron-binding properties and to test their antibacterial activity against a panel of pathogenic organisms.

Techniques involved: The work will involve synthetic organic chemistry, UV/vis-spectroscopy and basic microbiology.

Background of the student: Some experience in synthetic chemistry and knowledge of basic microbiological techniques would be of advantage.