The Development of Metallohydroxamates as Novel Anti-Bacterial and Anti-Leishmanial Agents

Since the initial development and clinical use of antibiotics, there has been a steady and alarming increase in the levels of antibiotic resistant bacterial infections arising worldwide. The reduced efficacy of antibiotics coupled to the lack of new classes of antibiotics being developed, may result in antibiotic resistance infections rising to epidemic levels.

The decrease in new antibiotic discovery has resulted in increased interest in repurposing and repositioning of previously developed drugs as effective anti-bacterial treatments. The use of metals in medicine is not a new phenomenon as they have been used in medicine for thousands of years. Nonetheless the scientific community has not realised the full medicinal potential of metal complexes. Novel complexes will offer new treatment to current diseases and provide alternatives to purely organic treatments.

Bismuth had been used in the 18^th Century for the treatment of many diseases and its anti-bacterial properties were well documented. It has also been shown to have anti-fungal, anti-leishmanial and anti-bacterial properties and is currently now used as part of the new treatment for H. pylori infections of the stomach. Gallium compounds are currently being used clinically as diagnostic and therapeutic agents. Gallium’s similarities to iron allows for its incorporation into certain iron binding proteins, disrupting the natural function of the proteins and leading to adverse downstream effects. Antimony containing drugs have become the first line drugs used in the clinic for the treatment of leishmaniasis.

Hydroxamic acids are a family of important bio-ligands of general formula RCONR’OH. They are known for their ability to chelate to metals and metalloenzymes, often inhibiting many important biological processes involving urease, lipoxygenases and peptide deformylase enzymes. They have also been exploited as siderophores, due to their ability to efficiently bind iron. For this reason they have shown activity against a range of conditions including cancer, malaria, tuberculosis, cardiovascular disease, HIV, Alzheimer disease and fungal infections.

Chapter 1 provides an introduction into the role some of the previously mentioned metals play in medicine currently and in the past. The ever increasing problem of bacterial resistance will be discussed, with some of the important mechanisms of resistance and acquiring of resistance explained. An introduction to some important bacteria and the diseases they cause will also be described and hydroxamic acids as an important class of bioligands will be discussed. H. pylori is a microaerophilic bacteria which causes dyspepsia, peptic ulcer and is one of the main causative agents for the development of gastric cancer. Due to bacterial resistance to many antibiotics, current treatment is failing and consequently, the use of bismuth containing quadruple therapies are increasing as a first-line treatment recommendation in many countries. Chapter 3 focuses on development of novel bismuth hydroxamate complexes as structurally well-defined potential treatments for H. pylori.

Chapter 4 looks to further develop a novel class of bismuth hydroxamate complexes which have activity against a broader range of bacteria, beyond H. pylori.

Chapter 5 describes the synthesis of novel bismuth and gallium retro hydroxamate complexes which may be used as anti-bacterial agents with activity against both Gram-positive and Gram-negative bacteria. These compounds are also developed to investigate if they have activity against current antibiotic resistant bacteria.

Finally chapter 6 details the development of novel antimony hydroxamate compounds and an investigation of their potential to act as anti-leishmanial agents.