A molecular design trick called polarity reversal can make useless antibiotics kill 100 percent of multi-drug resistant superbugs in mice.
April 26, 2026
Original Paper
N-Terminal Polarity Reversal of Cysteine-Terminated Peptides: A Strategy to Develop Potent Metallo-β-Lactamase Inhibitors with In vivo Efficacy
SSRN · 6624263
The Takeaway
Multi-drug resistant bacteria have rendered many of our strongest medicines completely ineffective. These new peptide inhibitors work by blocking the enzymes that superbugs use to shred antibiotics. They were designed by flipping the electrical orientation of specific amino acids to create a tighter bond with the target. In tests on living mice, the treatment restored the power of old drugs and saved every single infected animal. This approach provides a new blueprint for beating infections that were previously considered untreatable.
From the abstract
The emergence of metallo-β-lactamase (MBL)-producing pathogens poses a critical threat to the efficacy of β-lactam antibiotics, with no clinically approved inhibitors currently available. Here, we report a rational design strategy for potent MBL inhibitors based on a “polarity reversal” of the N-terminus of cysteine-terminated peptides. A series of N-terminally protected di- and tripeptides were synthesized and evaluated. Two lead compounds, Fmoc-FFC and Fmoc-MC, emerged as potent, competitive i