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

Nature communications 2023 Sep 09

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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. © 2023. Springer Nature Limited.

Citation

Ladan Khodaparast, Laleh Khodaparast, Guiqin Wu, Emiel Michiels, Rodrigo Gallardo, Bert Houben, Teresa Garcia, Matthias De Vleeschouwer, Meine Ramakers, Hannah Wilkinson, Ramon Duran-Romaña, Johan Van Eldere, Frederic Rousseau, Joost Schymkowitz. Exploiting the aggregation propensity of beta-lactamases to design inhibitors that induce enzyme misfolding. Nature communications. 2023 Sep 09;14(1):5571