War on 'superbugs'

Ian Chopra on developments at Leeds's Antimicrobial Research Centre

Before the introduction of antibiotics in the 1940s many people died from bacterial infections. The advent of antibiotics completely changed this since physicians were able to cure diseases for which they had only been able to provide ameliorative, and largely ineffective, therapy.

Not long after the clinical introduction of antibiotics, reports of bacterial resistance began to appear. Nevertheless, the apparent ease with which new antibiotics were discovered and developed between 1950 and 1970 tended to minimise concern because new antibiotics always appeared in time to provide cures for diseases caused by resistant bacteria.

Recent developments have changed this complacent view. Antibiotics in use today attack bacteria by interfering with the biosynthesis of proteins, DNA, or essential cell wall components. Bacteria have fought back by decreasing the permeability of their cell membranes to reduce drug access, producing proteins that pump drugs rapidly out of their cells, acquiring enzymes to inactivate drugs, or altering the target molecules within the cell to protect these sites from drug action. These defences are a response to the selective pressures exerted by the use of antibiotics, and resistance arises either by mutations in genes that encode drug targets, or by acquisition of whole genes and gene sets from other resistant bacteria. Antibiotic resistance has led to the selection of so-called "superbugs", bacteria which are frequently resistant to more than one type of antibiotic.

There are several examples of "superbugs". Strains of Staphylococcus aureus have now emerged that are resistant to every known antibiotic except vancomycin. These strains, which have been designated MRSA (methicillin-resistant S. aureus), are responsible for wound and systemic infections, particularly in hospitalised patients. At the same time, multiple resistant strains of Streptococcus pneumoniae and Mycobacterium tuberculosis have appeared, raising the possibility of incurable bacterial pneumonia and tuberculosis.

Furthermore, many strains of Pseudomonas aeruginosa and Enterococcus faecalis, two species of bacteria that are commonly responsible for hospital-acquired infections in patients with underlying conditions such as cancer, have become resistant to most known antibiotics. The threats to public health and increased medical and nursing costs associated with the emergence of these antibiotic-resistant "superbugs" have been highlighted by several governments and the World Health Organisation.

Paradoxically, there has been a parallel decline in the discovery of new antibiotic classes, reflecting a decreasing industrial commitment. This is primarily the result of commercial factors whereby promising markets in the 1970s and 1980s were thought to be found not in drugs against bacterial infections, but in those for cancer, diabetes, arthritis. obesity and cardiovascular, psychiatric and neurological diseases.

Fortunately research on antibacterial agents has resumed at many pharmaceutical companies. The Antimicrobial Research Centre at the University of Leeds has been created to add further impetus to the discovery and development of new antibiotics. The ARC, created in October 1996, is a centre for scientific excellence within the university. It comprises some 45 principal investigators from several departments with related interests in the discovery and development of novel anti-infective drug therapies. Expertise includes microbiology, molecular biology, protein purification and crystallography and medicinal chemistry. The ARC also provides a valuable training ground for research students and postdoctoral fellows with interests in infectious diseases and medicinal chemistry.

The centre builds upon existing expertise at Leeds by seeking funding from industry, the European Community, research councils and charitable organisations to support research on new antibacterial agents and chemotherapeutic strategies. Principal investigators in ARC already receive substantial research funding for the study of antibiotics, infectious diseases and the molecular biology of pathogenic bacteria. However, the ARC intends to attract at least a further Pounds 6 million in research funding over the next three years to underpin its research objectives. In order to assist the discovery and development of new antibacterial drugs, collaborative research programmes with industry will be an important focus.

An important "state-of-the-art" approach to be undertaken by ARC scientists will be rational, structure-based drug design leading to the synthesis of new chemical inhibitors that may become future antibiotics. Structure-based drug design involves determining the three-dimensional structure of a bacterial target molecule, followed by computer modelling to build a chemical that precisely fits the target and inhibits its activity. Recent bacterial genome sequencing initiatives, that seek to define the complete genetic make-up of several pathogenic bacteria will substantially assist the structure-based drug design approach by identifying new molecular targets for inhibition.

The work of the ARC will contribute to research on overcoming the problems created by antibiotic-resistant pathogenic bacteria. However, the relentlessly evolving survival strategies of bacteria will continue to challenge both ARC scientists and others in institutions around the world for many years to come.

Ian Chopra is director of the Antimicrobial Research Centre at the University of Leeds.