2003 IRISH SCIENTIST YEAR BOOK

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University College Dublin
Margaret Worrall
Developing new targets for antibiotics

Electron micrograph of Staphylococcus aureus cells

Ever since antibiotics became available in the 1950's, they have been hailed as miracle drugs - magic bullets able to destroy disease-causing bacteria. However, antibiotic resistance is now an increasing worldwide health problem and according to the Centers for Disease Control and Prevention (CDC), virtually all significant bacterial infections in the world are becoming resistant to the antibiotic treatment of choice. MRSA (Methicillin resistant staphylococcus aureus) is a particular problem, causing many nosocomial i.e. hospital borne infections and estimated to be responsible for 5000 deaths in Britain per year (reliable data is not available for Ireland). All this has occurred due to widespread use of existing antibiotics, leading to reduced target susceptibility to whole classes of antibiotics. Therefore, there is a pressing need to develop not just new variations on existing drugs, but also completely new microbial targets.

Identifying essential enzymes and processes in bacteria that are either unique or are substantially different from the host counterpart provides the best opportunity to elucidate new antibiotic targets. Two such enzyme targets that have emerged in the past few years are found in the pathway used by all cells to make Coenzyme A (CoA) from the vitamin pantothenic acid or B5. CoA is essential for numerous metabolic pathways including those central to the production of energy from glucose and fats. The cell can recycle CoA to some extent, but if it can no longer make CoA then it will ultimately die. The UCD group has worked on human CoA biosynthetic enzymes and shown that the last two pathway steps are actually catalysed by a single enzyme with two activities. However, in bacteria two separate enzymes carry out these steps and they are unrelated to the bifunctional human counterpart. Hence there is now much interest in developing drugs to block only the bacterial enzymes, and in doing so selectively kill the bacterial cells. In UCD, we are collaborating with a US pharmaceutical company to develop this approach. In particular staphylococcal enzymes are being targeted because resistance in this organism presents an increasing challenge for human health.

Contact: Dr Margaret Worrall, Department of Biochemistry and Conway Institute, UCD
E-mail: [email protected]