Exploiting the aggregation propensity of beta-lactamases to design inhibitors that induce enzyme misfolding

Nat Commun. 2023 Sep 9;14(1):5571. doi: 10.1038/s41467-023-41191-z.


There is an arms race between beta-lactam antibiotics development and co-evolving beta-lactamases, which provide resistance by breaking down beta-lactam rings. We have observed that certain beta-lactamases tend to aggregate, which persists throughout their evolution under the selective pressure of antibiotics on their active sites. Interestingly, we find that existing beta-lactamase active site inhibitors can act as molecular chaperones, promoting the proper folding of these resistance factors. Therefore, we have created Pept-Ins, synthetic peptides designed to exploit the structural weaknesses of beta-lactamases by causing them to misfold into intracellular inclusion bodies. This approach restores sensitivity to a wide range of beta-lactam antibiotics in resistant clinical isolates, including those with Extended Spectrum variants that pose significant challenges in medical practice. Our findings suggest that targeted aggregation of resistance factors could offer a strategy for identifying molecules that aid in addressing the global antibiotic resistance crisis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents* / pharmacology
  • Inclusion Bodies*
  • Monobactams
  • R Factors
  • beta-Lactamase Inhibitors / pharmacology
  • beta-Lactamases


  • Anti-Bacterial Agents
  • Monobactams
  • beta-Lactamase Inhibitors
  • beta-Lactamases