Proof of Concept of Amoxicillin Through the Looking-Glass: A Computational Investigation on Structural Aspects of Mirror Life

Background statement In the mid of 1800 Louise Pastor pioneeringly opened the debate around the so-called mirror life, today referring to purely enantiomeric systems – e.g. left-handed carbohydrates and nucleotides, and right-handed proteins and amino acids (1, 2). Recently, Adamala and co-workers summarized and rationalized the major concerns a mirror organism may pose. In particular, the authors warned that mirror bacteria, i.e. enantiomeric microorganisms, may pose an unprecedented threat to life, as they are likely able to evade immune responses and exhibit enhanced fitness and antibiotic resistance (3). The authors also claimed for a broad and interdisciplinary engagement to foster a responsible and informed approach to managing a technology that may pose unprecedent risks. In this context, using amoxicillin as a proof-of-principle, we present our findings, methods, and raw data to offer a shared and completely open foothold to promote further research, driven by i) the necessity to approach this issue from an interdisciplinary standpoint, and ii) the critical importance of open, collaborative, and unrestricted science in the face of such a global threat. Disclaimer This research, its methods, and outcomes are meant to provide an evolving open forum for cumulative research and discussion on the risks associated with mirror microorganisms. This record includes: A document with the overview of the proof-of-concept study, details about the methods applied and outcomes Raw data including the 3D model of mirror image of amoxicillin’s target under investigation, the calculated binding architecture of amoxicillin with its native and D-counterpart target, and MD trajectories of apo and amoxicillin-bound native and D-counterpart protein References 1. Z. M. Wang, W. L. Xu, L. Liu, T. F. Zhu, A synthetic molecular system capable of mirror-image genetic replication and transcription. Nature Chemistry 8, 698-704 (2016). 2. A. J. Lander, Y. Jin, L. Y. P. Luk, D-Peptide and D-Protein Technology: Recent Advances, Challenges, and Opportunities. Chembiochem 24, (2023). 3. K. P. Adamala et al., Confronting risks of mirror life. Science, eads9158 (2024).