I attended the 6th Annual Meeting of the Boston Area Resistance Network Meeting this past Friday. A fabulous meeting. Kudos to the organizers. I was particularly riveted by a presentation from Erin Duffy, CSO, of Melinta Pharmaceuticals: "On the design and optimization of pyrrolocytosines." It was a beautiful example of structure-guided design. Melinta was originally called Rib-X Pharmaceuticals. Rib-X was founded on the idea that new drugs could be developed based on the structure of the 50S ribosome (therefore Rib-X) solved by Tom Steitz and Peter Moore. A series of compounds were synthesized to explore a binding site in the 50S ribosome that were not known to be engaged by existing natural products. Therefore, ribosome modifying enzymes conferring resistance through modification of this binding site would presumably not have previously evolved. A point was made of exploring the empty space within the ribosome. I don't remember all of the details, but it went along the lines of by compound 500 had great Gram-positive activity; by compound 1000 had great Gram-negative and Gram-positive activity inclusive of Acinetobacter and Pseudomonas, Interestingly, the molecular characteristics associated with Gram-negative penetrance did not follow eNTRy rules. By compound 2000, toxicity issues had been worked out inclusive of mammalian testing. So seemingly a really promising first in class agent. The final slide for this impressive development effort was a picture of the research group and then a comment that they were all let go the previously week. The company redirected all of its efforts to sales for approved agents and pulled out of discovery efforts. This follows on Achaogen eliminating their discovery program after approval of plazomicin, which follows on Novartis exiting the antibiotic development space. Disconcerting juxtaposition of success and abandonment.
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