Medicine

Anti-resistance measures

CombiGyrase, a European research project on antibiotics, is providing hope in the battle against bacterial resistance, the bane of western hospitals…

Gyrase is an enzyme of vital importance to bacteria, though not present in humans. It is therefore an ideal ‘target’ for the development of antibiotics (represented here in coloured balls). Gyrase is an enzyme of vital importance to bacteria, though not present in humans. It is therefore an ideal ‘target’ for the development of antibiotics (represented here in coloured balls).

The enemy is known. It can be tracked down, but eludes tracking with increasing regularity. ‘It’ refers, for instance, to MRSA or methicillinresistant Staphylococcus aureus (golden staph) and other superbugs or pathogenic bacteria that have become resistant to antibiotics. ‘The problem is particularly acute in the hospital environment, most notably in intensive care units,’ explains Lutz Heide, professor at the University of Tübingen (DE), and coordinator of the CombiGyrase project. ‘Elderly patients and those who have undergone a transplant or prosthetic implant surgery are most at risk.’ The problem, closely monitored in developed countries, has existed for half a century, but has grown in recent years. ‘We are finding increasing resistance to our ultimate weapons in antibiotic terms – methicillin and vancomycin. Pathogenic microbes, particularly gram-positive bacteria, including Enterococcus and Staphylococcus, have acquired a level of resistance that can transform otherwise easily treatable illnesses into septicemias and pneumopathies that are frequently fatal. This resistance has become one of the main causes of death among vulnerable groups.’

Inequality in relation to microbes and research

On the resistance front, the situation is by no means uniform. Hence, the European Antimicrobial Resistance Surveillance System (EARSS), which is responsible for monitoring bacterial resistance phenomena across 31 countries, and has recorded levels of resistance of over 50% for certain bacteria in certain countries. ‘This is quite a good reflection of prescription practices. The more antibiotics are (over)- consumed, the greater the selective pressure on microbes, and the greater the resistance induced.’ It is Darwinian… and this explains why there must be no let-up in our search for new molecules, while limiting the use of existing ones to cases where they are genuinely needed.

The big pharmaceutical companies have, in general, reduced if not suspended their research in this area. When one considers the astronomical cost of developing new drugs, it becomes clear that it is more profitable to invest in the battle against diabetes, hypertension or other conditions that have to be treated throughout a lifetime, than to find a new antibiotic that will be prescribed from time to time.

Gyrase in the line of sight

However, some cutting-edge biotech SMEs have not lowered their sights. Two such companies are part of the CombiGyrase consortium, which in total comprises seven partners from five countries, and is funded by the Commission to the tune of € 1.56 million over three years. Its aim is to use an unpublished method to develop new antibiotics.

CombiGyrase can boast three successes. The first is to have perfected a technique that increases, through genetic engineering, the chances of discovering new antibiotics from natural compounds. The method can be transposed on an industrial scale and permits significant time saving in the research of potential molecules.

The second is to have selected, thanks to this strategy, some 50 or so compounds in the aminocoumarins class. These are powerful inhibitors of an enzyme called gyrase, which is crucial to the multiplication of bacteria. Gyrase is an enzyme of vital importance to bacteria, though not present in humans. It is therefore an ideal ‘target’ for the development of antibiotics (represented here in coloured balls). There are many potential candidates for a new antibiotic for which interaction with the ‘target’ is completely proven.

Finally, the project has developed a gyrase inhibitor compound – Simocyclinone – the active mechanism of which is both unpublished and promising. Something to fuel hopes of discovering new antibiotics to combat multi-resistant pathogens and fortify Europe in its support for the development of emerging technologies. ‘With cutting-edge groups and an effective network of researchers, Europe has taken the lead in this field,’ concludes Lutz Heide.

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