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This site provides free access to tools developed by Idorsia Pharmaceuticals Ltd, Allschwil (Switzerland) for it's own drug discovery and development.

The company provides these pre-competitive tools without commercial interest. For details, please check the open license terms of each software.

While we cannot provide support, we are keen to receive your constructive feedback. We may also be interested in joint future development.

Publication

Bacteria Retention Model - Test your structures

The increasing prevalence of difficult or even impossible-to-treat infections caused by multidrug resistant Gram-negative bacteria has led to a healthcare crisis, necessitating the search for new drugs with novel modes of action. Gram-negative bacteria are composed of two membranes with orthogonal properties and are equipped with powerful efflux pumps in order to prevent any xenobiotic molecules from accumulating inside the cell. Therefore, the design of drugs reaching the cytoplasm to elicit their antibacterial effect in Gram-negative bacteria has been identified as a major hurdle on the way to developing novel Gram-negative antibiotics.

To address the problem of cytoplasmic drug accumulation in a broader sense, we have developed a method that allows for the direct measurement of small molecule retention by Gram-negative bacteria, irrespective of antibacterial activity. A set of more than 13’000 structurally diverse compounds was tested for retention by TolC mutated E. coli. 49% of the compounds could be detected by MS and clearly classified. Of these, 45% were found to be retained by the bacteria, while 55% were not. The screening results were then used to train a computational prediction tool based on a machine learning algorithm. It could be experimentally confirmed that this tool classifies unknown compounds correctly as retention Positive in 77.8% of cases, and as Negative in 74.4%.

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