Development of Novel Antimicrobial Drugs for Mycobacterium tuberculosis
Thioredoxin reductase (TrxR) is an enzyme essential for the maintenance of redox homeostasis in most cells and plays a particular role in combating oxidant challenges. It has been shown that TrxR of Mycobacterium tuberculosis (Mtb) is essential for the survival of the bacteria and is a potential new drug target. Mtb is the causative agent of tuberculosis, a disease that cause around 1.5 million deaths in 2013 due to the drug resistant to current antibiotics. The active site of Mtb TrxR differs significantly from that of the mammalian counterpart, which is reflected in the kinetic properties of the enzymes. In a recent study, it was reported that the organo-gold compound, auranofin, was found to be active against both the replicating and non-replicating Mtb. It is the intention of this project to build upon these findings with the aim of developing novel inhibitors, which display good potency and specificity toward Mtb TrxR by synthesizing organo-gold compounds as potential redox cyclers which incorporate the key features of the Mannich bases that ensure binding to the two cysteine residues in the active site of the bacteria TrxR. The activity of these compounds will be assessed against TrxR. Analysis of the structure-activity relationship will direct the design and synthesis of second-generation compounds with potentially improved inhibitory characteristics. It is proposed to continue this iterative approach to obtain effective inhibitors of Mtb TrxR, which also have good potency against Mtb. Such compounds will act as leads in the development of novel antitubercular drugs.
The student will learn a range of different experimental techniques, including medicinal chemistry, metabolomics and molecular biology, enabling the student to gain expertise in a number of vital skills for laboratory research. The student will take part in the University Graduate School and Faculty Doctoral Research Development Programme; in addition to these training programmes and the subject specific skills listed above, the student will gain important transferable skills (e.g. presentation skills, scientific writing and employability skills) to aid in future career progression. The student will be encouraged to join learned societies (e.g. British Pharmacological Society, British Society for Antimicrobial Chemotherapy), which provide excellent support for students in terms of training workshops and regular meetings to disseminate and publish their research.
The Studentship consists of a fee waiver and a stipend of £16,000 per annum. Successful candidates will be expected to undertake some teaching duties.
Harbut et al. (2015). Auranofin exerts broad-spectrum bactericidal activities by targeting thio-
Redox homeostasis. PNAS 112, 4453-4458.
Chakraborty et al. (2013) Para-aminosalicyclic acid acts as an alternative substrate of folate
Metabolism in Mycobacterium tuberculosis. Science 339, 81-9.
Raheem et al. (2011) Total synthesis of 3,5-O-dicaffeolyquinic acid and its derivatives.
Tetrahedron Lett 52, 7175-7177
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FTE Category A staff submitted: 24.80
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