Stephan Hacker7h ago

How can we develop new antibiotics against the most devastating infections with antibiotic-resistant Gram-negative bacteria?

Thomas Clairfeuille gave an inspiring lecture on this topic in his @LED3hub Lecture, in which he described the discovery and development of the antibiotic zosurabalpin against carbapenem-resistant Acinetobacter baumannii (CRAB). (1/7)

https://www.nature.com/articles/s41586-023-06873-0

Show threadStephan Hacker7h ago
He started with the interesting insight, that synthetic compounds can have a big advantage over natural compounds for the development of antibiotics as they have not already undergone a long history of evolutionary selection that can lead to resistance development in nature. "Resetting the clock on resistance". (2/7)
Show threadStephan Hacker
He then talked about the discovery of zosurabalpin based on the screen of a library of cyclic tripeptides and gave important insights into all the challenges that they faced and resolved during the development of this compound. (3/7)
5:26amWeb
Show threadStephan Hacker7h ago
Next, he discussed the elucidation of the mechanism-of-action of zosurabalpin as an inhibitor of LPS transport using resistance development assays in combination with radioligand binding and functional assays. (4/7)
Show threadStephan Hacker7h ago
He then presented the structural elucidation of the binding of zosurabalpin to the LPS transport complex using cryoEM, which gave exctiting insights, why the compound is such a potent antibiotic and how resistance could develop. (5/7)
Show threadStephan Hacker7h ago
He finished with an interesting glimpse into the further optimization of the zosurabalpin scaffold using structure-guided design to result in amazing potency and broadest activity against the most resistant clinical strains. (6/7)
Show threadStephan Hacker7h ago

He also hinted at a new class of synthetic antibiotics that is in current development at Roche. Hopefully there are many more new antibiotics in the future. (7/7)

#Antibiotics #DrugDiscovery #DrugDevelopment #ChemBio #Chemistry #cryoEM #AMR #Resistance #Bacteria #SAR #Synthesis #Zosurabalpin