Prioritisation of potential drug targets against Bartonella bacilliformis by an integrative in-silico approach

Abstract

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.

Integrating diverse layers of omic data to identify novel drug targets in Listeria monocytogenes

“…Our analysis began by classifying all the domain structures of Listeria monocytogenes, including our own generated homologybased models and those directly retrieved from PDB, according to their structural druggability. For comparison, we also calculated the DS for all ligand-bound structures in a nonredundant subset of PDB (PDB95), revealing an important enrichment of druggable pockets in the Listeria models (Figure 2) in line with previous results in other pathogenic bacteria (Defelipe et al, 2016;Ramos et al, 2018;Farfán-López et al, 2020). Afterward, we grouped the proteins, according to how their structure was retrieved and their DS, into four categories.…”

Mining the Flavoproteome of Brucella ovis, the Brucellosis Causing Agent in Ovis aries

“…Up to 17 of the flavoproteins predicted as potentially virulent factors in B. ovis belong to the core proteome of Brucella (or lack in a single species), and are already noticed as involved in the infection process of different pathogens ( Table 3 ; Tables SP6 and SP7). Among them we can highlight the following: (i) Msr that maintains bacterial membrane integrity and contributes to adhesion with eukaryotic cells ( 59 , 89 ); (ii) two D-amino acid dehydrogenases that could play a pleiotropic role in the production of important virulence factors and support pathobiological exclusive functions for different isoforms within an organism ( 90 , 91 ); (iii) one isovaleryl-CoA dehydrogenase involved in vegetative growth, conidiation, and virulence of plant fungal pathogens ( 92 ); (iv) one glutamate synthase involved in chronic persistence of B. abortus infection in mice ( 51 ); (v) one cob(II)alamin reductase conserved in most alphaproteobacteria and whose deletion in B. abortus affects the pathogen survival ( 93 ); (vi) two tRNA methyltransferases with role in virulence, stress response, growth, and antibiotic susceptibility pathways ( 94 ); and (vii) NrdI, essential for the assembly of several subunits of class Ib ribonucleotide reductases expressed under oxidative stress and iron-limited growth conditions ( 95 ).…”

From Genome to Drugs: New Approaches in Antimicrobial Discovery

“…Our group has developed a fast whole genome approach for druggability prediction based on the open-source algorithm fpocket ( http://fpocket.sourceforge.net/ ) ( Guilloux et al, 2009 ), which combines several physicochemical descriptors to estimate the druggability of the pockets present in proteins. This approach was extensively tested, both on experimental structures and homology-based models, in the context of whole proteome target search studies in our previous works on the subject ( Radusky et al, 2014 ; Defelipe et al, 2016 ; Ramos et al, 2018 ; Sosa et al, 2018 ; Farfán-López et al, 2020 ). Based on previous analysis of the druggability score distribution, for all pockets that host a drug-like compound in the Protein Data Bank ( Sussman et al, 1998 ), we have classified pockets into four categories: non-druggable (ND), poorly druggable (PD), druggable (D), and highly druggable (HD).…”

“…High case-fatality rates as 40–88% have been described in the Oroya fever phase in patients without any antibiotic treatment. Even with timely antibiotic treatment, the fatality rate is around 11% ( Farfán-López et al, 2020 ). The chronic phase of Carrion’s disease is characterized by the development of dermal eruptions known as Peruvian warts and commonly present on the head and extremities.…”

“…In Farfán-López et al (2020) , our group participated in a work that combined the efforts of scientific groups from Argentina, Brazil, and Peru to perform an integrative genomic-scale data analysis, which allowed us to shortlist a set of proteins that could serve as attractive targets for new antimicrobial discovery projects against Bb. This study was based on the genomic analysis of Bb USM-LMMB 07, firstly isolated in 2011 during an outbreak in Carmen de la Frontera district, Huancabamba Province, Piura ( Guillen et al, 2016 ).…”