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BACKGROUND Carrion's disease (CD) is a neglected biphasic illness caused by Bartonella bacilliformis, a Gram-negative bacteria found in the Andean valleys. The spread of resistant strains underlines the need for novel antimicrobials against B. bacilliformis and related bacterial pathogens. OBJECTIVE The main aim of this study was to integrate genomic-scale data to shortlist a set of proteins that could serve as attractive targets for new antimicrobial discovery to combat B. bacilliformis. METHODS We performed a multidimensional genomic scale analysis of potential and relevant targets which includes structural druggability, metabolic analysis and essentiality criteria to select proteins with attractive features for drug discovery. FINDINGS We shortlisted seventeen relevant proteins to develop new drugs against the causative agent of Carrion's disease. Particularly, the protein products of fabI, folA, aroA, trmFO, uppP and murE genes, meet an important number of desirable features that make them attractive targets for new drug development. This data compendium is freely available as a web server (http://target.sbg.qb.fcen.uba.ar/). MAIN CONCLUSION This work represents an effort to reduce the costs in the first phases of B. bacilliformis drug discovery.

Toll-like receptors (TLRs) are transmembrane proteins that are key regulators of innate and adaptive immune responses, particularly TLR4, and they have been identified as potential drug targets for the treatment of disease. Several low-molecular-weight compounds are being considered as new drug targets for various applications, including as immune modulators. Mygalin, a 417 Da synthetic bis-acylpolyamine, is an analog of spermidine that has microbicidal activity. In this study, we investigated the effect of mygalin on the innate immune response based on a virtual screening (VS) and molecular docking analysis. Bone marrow-derived macrophages and the cell lines J774A.1 and RAW 264.7 stimulated with lipopolysaccharide (LPS) were used to confirm the data obtained in silico. Virtual screening and molecular docking suggested that mygalin binds to TLR4 via the protein myeloid differentiation factor 2 (MD-2) and LPS. Macrophages stimulated by mygalin plus LPS showed suppressed gene expression of tumor necrosis factor (TNF-α), interleukine 6 (IL-6), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), as well as inhibition of signaling protein p65 of the nuclear factor κB (NF-κB), resulting in decreased production of nitric oxide (NO) and TNF-α. These results indicate that mygalin has anti-inflammatory potential, being an attractive option to be explored. In addition, we reinforce the importance of virtual screening analysis to assist in the discovery of new drugs.

Mine tailings are produced by mining activities and contain diverse heavy metal ions, which cause environmental problems and have negative impacts on ecosystems. Different microorganisms, including yeasts, play important roles in the absorption and/or adsorption of these heavy metal ions. This work aimed to analyze proteins synthesized by the yeast Yarrowia lipolytica AMJ6 (Yl-AMJ6), isolated from Andean mine tailings in Peru and subjected to stress conditions with common heavy metal ions. Yeast strains were isolated from high Andean water samples impacted by mine tailings from Yanamate (Pasco, Peru). Among all the isolated yeasts, the Yl-AMJ6 strain presented LC50 values of 1.06 mM, 1.42 mM, and 0.49 mM for the Cr+6, Cu+2, and Cd+2 ions, respectively. Proteomic analysis of theYl-AMJ6 strain under heavy metal stress showed that several proteins were up- or downregulated. Biological and functional analysis of these proteins showed that they were involved in the metabolism of proteins, nucleic acids, and carbohydrates; response to oxidative stress and protein folding; ATP synthesis and ion transport; membrane and cell wall; and cell division. The most prominent proteins that presented the greatest changes were related to the oxidative stress response and carbohydrate metabolism, suggesting the existence of a defense mechanism in these yeasts to resist the impact of environmental contamination by heavy metal ions.

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