Gu, J; Agarwal, PK; Bonomo, RA; Haider, S; (2025) Evolutionary Dynamics and Functional Differences in Clinically Relevant Pen β-Lactamases from Burkholderia spp. Journal of Chemical Information and Modeling , 65 (10) pp. 5086-5098. 10.1021/acs.jcim.5c00271.

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Abstract

Antimicrobial resistance (AMR) is a global threat, with Burkholderia species contributing significantly to difficult-to-treat infections. The Pen family of β-lactamases are produced by all Burkholderia spp., and their mutation or overproduction leads to the resistance of β-lactam antibiotics. Here we investigate the dynamic differences among four Pen β-lactamases (PenA, PenI, PenL and PenP) using machine learning driven enhanced sampling molecular dynamics simulations, Markov State Models (MSMs), convolutional variational autoencoder-based deep learning (CVAE) and the BindSiteS-CNN model. In spite of sharing the same catalytic mechanisms, these enzymes exhibit distinct dynamic features due to low sequence identity resulting in different substrate profiles and catalytic turnover. The BindSiteS-CNN model further reveals local active site dynamics, offering insights into the Pen β-lactamase evolutionary adaptation. Our findings reported here identify critical mutations and propose new hot spots affecting Pen β-lactamase flexibility and function, which can be used to fight emerging resistance in these enzymes.

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