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UrduIn a study published this month in Antimicrobial Agents and Chemotherapy, researchers at Osaka University have produced new insights into the structure of a particular bacterial protein known as an efflux pump. This protein is involved in antibiotic resistance and its structure influences the ability of drugs to target it.
Many conventional antibiotics, such as penicillin or erythromycin, work by making their way into a bacterial cell. Once there, the antibiotic prevents the cell from working properly by interfering with its molecular machinery. From a bacterium’s perspective, this is where the efflux pump comes in handy; by pumping any compounds that are harmful to it (like antibiotics) out of the cell using an efflux pump, the bacterium can protect itself from them. Bacteria that have mutated to become particularly resistant to antibiotics often have many of these efflux pumps on their surface.
To counter this defense, researchers have produced a class of drugs that stop efflux pumps from working. These drugs, called efflux pump inhibitors, are effective at preventing the activity of some but not all types of efflux pump. Understanding how these drugs bind to efflux pumps is essential for understanding how they work, and so to producing new drugs.
Lead author Seiji Yamasaki says “We discovered the spatial characteristics of the inhibitor binding site in a bacterial efflux pump. We have succeeded in this analysis by examining the protein structure and by generating and analyzing a series of mutant pumps.”
By using genetic manipulation to change the position of a “bulky” amino acid called tryptophan, the researchers were able to show which positions were important for the ability of a specific inhibitor called ABI-PP to bind to, and prevent the action of, a specific efflux pump called MexB. Specifically, they found that bulky mutations to the top and the middle of the binding site were particularly effective at preventing ABI-PP binding.
Senior author Kunihiko Nishino says “Our results highlight that the overall spatial characteristics of the inhibitor binding site are more relevant to prevention of inhibition than single mutations. We hope that this work will inform the rational design of drugs that target efflux pumps, helping us to eliminate drug-resistant bacteria in the future.”
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The article, “Spatial Characteristics of the Efflux Pump MexB Determine Inhibitor Binding,” was published in Antimicrobial Agents and Chemotherapy at DOI: https://journals.asm.org/doi/10.1128/aac.00672-22
About Osaka University
Osaka University was founded in 1931 as one of the seven imperial universities of Japan and is now one of Japan’s leading comprehensive universities with a broad disciplinary spectrum. This strength is coupled with a singular drive for innovation that extends throughout the scientific process, from fundamental research to the creation of applied technology with positive economic impacts. Its commitment to innovation has been recognized in Japan and around the world, being named Japan’s most innovative university in 2015 (Reuters 2015 Top 100) and one of the most innovative institutions in the world in 2017 (Innovative Universities and the Nature Index Innovation 2017). Now, Osaka University is leveraging its role as a Designated National University Corporation selected by the Ministry of Education, Culture, Sports, Science and Technology to contribute to innovation for human welfare, sustainable development of society, and social transformation.
Website: https://resou.osaka-u.ac.jp/en
