Reviewer response for version 2

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The mortality rate and economic burden of infections caused by antimicrobial resistant pathogens are increasingly higher. This frustrating scenario emphasizes the urgent need for developing new antimicrobial drugs. We have previously addressed this problem by studying the antimicrobial activity of two novel iron-halide complexes, Fe(Hampy)2Cl4 (iron-tetrachloride) and Fe(Hampy)2Br4 (iron-tetrabromide). Both compounds showed bactericidal and antibiofilm activities against bacteria with an antimicrobial resistance phenotype. Herein, we used a proteomics approach to investigate the protein-expression profile of bacterial cells previously exposed to both iron-halide complexes. For this study, the Escherichia coli strain, BW25113, was used as a model to facilitate the rapid identification of deregulated proteins. Heat map analysis of the common deregulated proteins highlighted that both complexes caused downregulation of proteins associated with key metabolic pathways, biofilm formation, cell-envelope biogenesis, and iron ion binding. In addition, network study suggested that the most influential proteins of the tetrachloride activity were those involved in TCA cycle, oxidative phosphorylation, iron ion homeostasis and carbon/secondary metabolism. This protein-protein interaction analysis also hinted that the main drivers of the tetrabromide activity were proteins involved in translation, ribosomal biogenesis, and cell motility. The above results strongly suggested how the presence of different halide ligands could be used to generate compounds with potentially different molecular mechanisms. Importantly, the findings of this study can also be used as a reference to compare with the protein profile of a bacteria exposed to future variants of the iron-halide complexes.

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