Glyphosate, a herbicide, and fosfomycin, an antibiotic in clinical use- evidence of common selectable genotypes

The emergence of antimicrobial resistance (AMR) is increasingly linked to metabolic adaptation, yet the evolutionary routes underlying cross-resistance between structurally related compounds remain poorly understood. Here, whole genome sequencing (WGS) was used to analyse Klebsiella pneumoniae mutants evolved under sub-lethal glyphosate (GLP) or fosfomycin (FOS) exposure to determine how these stresses shape resistance and physiology. Sub-lethal GLP exposure increased FOS resistance, demonstrating cross-resistance between the two phosphonates. FOS-evolved mutants achieved high-level resistance through the accumulation of multiple mutations affecting the antibiotic target MurA, transport systems, and global metabolic regulation, producing a layered FOS resistance phenotype. In contrast, GLP-evolved mutants acquired similar functional classes of mutations but exhibited lower baseline FOS resistance, suggesting trade-offs between resistance and metabolic fitness. Further, analysis of FOS-evolved and GLP-evolved mutants across known bacterial GLP resistance mechanisms demonstrated a strong overlap. Comparative genomic analysis revealed a small, recurrent set of genes under selection in both evolutionary trajectories, with identical genomic loci repeatedly targeted, consistent with convergent evolution. Many of these changes were linked to central metabolism, redox balance, and cell surface regulation. For some isolates, a hypermutator phenotype was necessary to offset the potentially lethal effects of primary-target mutations through compensatory genomic adaptation. In conclusion, GLP and FOS select for shared adaptive networks that couple metabolic rewiring with AMR, revealing cross-resistance as an emergent property of global physiological reprogramming and providing mechanistic insight into ecological models of co-selection in environmental systems.

Fanning, S., Wall, K. D., Campbell, A., Marmion, M., Kilroy, A., Doyle, C., Marshall, H.

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