Scientists have discovered a target for the development of a drug to combat a bacterium that can cause chronic lung infection in hospitalised patients, immunocompromised individuals and people with cystic fibrosis.
The multidrug-resistant bacteria Pseudomonas aeruginosa infects the lung and promotes an accelerated decline of pulmonary function. It has been acknowledged as a serious threat by the Centres for Disease Control and Prevention and rated a critical priority by the World Health Organization.
The Fraunhofer International Consortium for Anti-Infective Research (iCAIR), led by Distinguished Professor Mark von Itzstein AO at Griffith University's Institute for Glycomics and Professor Dr Armin Braun at the Fraunhofer Institute for Experimental Medicine (ITEM) in Hannover, Germany, in collaboration with researchers at the Hannover Medical School established a joint research program that tackles antibiotic resistance development of Pseudomonas aeruginosa.
"Utilising human ex vivo precision-cut lung slices and lung cells as infection models, along with combined crystallography and biochemical studies, we were able to precisely characterise the molecular basis for the role of a certain enzyme in P. aeruginosa infection biology" says Dr Larissa Dirr, Institute for Glycomics Early Career Research Leader and co-senior author on a collaborative study with co-senior author Dr Jana Führing from Hannover Medical School.
"While the active site of the bacterial enzyme is very similar to the human enzyme, our now published study revealed a new functionally crucial allosteric site that is unique to the bacterial enzyme and identifies an important point-of-difference between the human and bacterial enzyme. This point-of-difference provides an excellent concrete starting point for the structure-based development of selective bacterial inhibitors." says Dr Larissa Dirr, lead researcher on this program.
"Currently we are in the process of using structure-based drug design to develop a selective inhibitor against Pseudomonas aeruginosa".
"Ultimately, as the allosteric site is conserved across bacterial enzymes, our aim is to use this knowledge to design a broad-spectrum antibiotic against Gram-negative and Gram-positive bacteria".
Institute for Glycomics Acting Executive Director Professor Michael Jennings says this discovery is a key breakthrough for the iCAIR Consortium.
"The alliance establishes a development platform that covers all the steps of a targeted drug development process from identifying potential points of attack, right through to drug design and efficacy testing".
"I have no doubt the developments of this study will illustrate the power of global collaboration and the translation of world-leading science to deliver novel drugs to the community".
Results have been published in mBio.
ABOUT
International Consortium for Anti-Infective Research (iCAIR) is a major international partnership between Australia's Institute for Glycomics and Germany's Fraunhofer Institute for Toxicology and Experimental Medicine in Hannover, the Institute for Clinical Biochemistry at the Hannover Medical School (MHH), and Helmholtz Centre for Infection Research.
The Consortium aims to discover new treatments to combat respiratory viruses including SARS-CoV-2, influenza virus and respiratory infection-causing bacteria and fungi.
Infectious diseases and antibiotic resistance are a global, and potentially deadly threat and there is an urgent need to develop new drugs and treatments to combat infection.
