Using an imaging technique called x-ray crystallography, a team of researchers from GlaxoSmithKline (GSK) captured a snapshot of the new compound latched on to the enzyme topoisomerase. This enzyme is part of the bacteria's internal machinery and helps the bacteria produce proteins and replicate. Stopping this enzyme prevents the bacteria from reproducing. Medicines, known as the quinolones, that target the enzyme have been successfully used as antibiotics since 1962, however bacteria are increasingly developing resistance to this class of drugs.
By looking at x-ray images, the team was able to demonstrate that the new investigational medicine attaches to the enzyme in a different place to quinolones, enabling it to stop the same bacteria that are resistant to these older treatments. The research is published today in the journal Nature, and is the result of two unique collaborations between GSK and the Wellcome Trust's Seeding Drug Discovery initiative and the U.S. Defense Threat Reduction Agency (DTRA).
"We already knew that targeting this enzyme was clinically proven to stop bacteria in their tracks, we just needed to be a bit more inventive in how we attacked it," said Michael Gwynn, from GSK's Infectious Diseases research group. "These images and the data showing the efficacy of this compound against a range of bacteria validate our approach, demonstrating that the enzyme can still be blocked even in bacteria already resistant to other antibiotics that work against this same enzyme."
The study also reports the potency of the new compound, called GSK 299423, against antibiotic-resistant strains of bacteria such as Staphylococus aureus, including methicillin resistance S. aureus (MRSA), and against gramnegative bacteria like E. coli, Pseudomonas, Klebsiella and Acinetobacter. Gram-negative bacteria are particularly difficult to attack as they have an outer membrane surrounding the bacterial cell wall, which interferes with drug penetration. New medicines must not only be toxic to the pathogen, but must first overcome the barriers to entry into the cell.
Commenting on the importance of the findings, Ted Bianco of the Wellcome Trust said: "This is an important step forward in the race against antibiotic resistance. By solving the new structure of this important bacterial enzyme, and understanding how these drugs work, the team has opened the door for targeted drug design of new antibiotics, which are urgently needed."
The particular compound from this study is one of a group that is currently being worked on in order to develop the best compounds in terms of efficacy and safety. This should help identify drug candidates that could be taken forward into early stage trials in humans.
Development of the new drug class to tackle gram-negative infections is supported as part of the Trust's Seeding Drug Discovery initiative. The collaboration provides GSK with a Â£4 million award from the Trust with GSK matching the contribution in staff, equipment, and other programme costs. The research collaborations with the Trust and with DTRA are aimed at developing an entirely new class of antibacterials to tackle hospital-acquired infections and potential biothreat outbreaks.
"The Wellcome Trust has recently announced a five-year extension to the Seeding Drug Discovery initiative, enabling us to continue to support drug development in areas of unmet medical need," added Rick Davis, Business Development Manager at the Wellcome Trust.
The rapidly increasing resistance of bacteria to antibiotics is a global issue, which can cause longer recovery times and hospitalisations, increased costs and rising mortality. It is estimated that each year about 25,000 people in the European Union die as a result of infections cause by multi-drug resistant bacteria.(2)
A study from the US estimated that patients with infections due to antimicrobial-resistant organisms increase the costs of care by between $6,000 and $30,000 per patient compared with patients with infections that are caused by bacteria susceptible to antimicrobials.(3)
Gram-negative bacteria are common causes of hospital-acquired infections like pneumonia and septic shock and are increasingly developing resistance to available antibiotics.
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About the Wellcome Trust
The Wellcome Trust is a global charity dedicated to achieving extraordinary improvements in human and animal health. It supports the brightest minds in biomedical research and the medical humanities. The Trust's breadth of support includes public engagement, education and the application of research to improve health. It is independent of both political and commercial interests.
1. Bax B, Chan P, Eggleston D et al. Type lla topoisomerase inhibition by a new class of antibacterial agents. Nature ; E-pub ahead of print publication.
2. European Centre for Disease Control and Prevention/European Medicines Agency Joint Working Group. The bacterial challenge: time to react. 2009.
3. Cosegrove, S. The Relationship between Antimicrobial Resistance and Patient Outcomes: Mortality, Length of Hospital Stay, and Health Care Costs. Clinical Infectious Diseases 2006; 42:S82â9