MM8-MULTI-OMICS DATA INTEGRATION APPROACH TO IDENTIFY ATTRACTIVE DRUG TARGETS IN LISTERIA MONOCYTOGENES

MIRANDA PALUMBO; EZEQUIEL SOSA; FEDERICO SERRAL; FLORENCIA CASTELLO; GUSTAVO SCHOTTLENDER; TANIA GORDILLO; SABRINA SOL BOCKOR; MARÍA MERCEDES PALOMINO; DARÍO FERNÁNDEZ DO PORTO

Córdoba

Congreso; SAMIGE 2022; 2022

Sociedad Argentina de Microbiología General

MM8-MULTI-OMICS DATA INTEGRATION APPROACH TO IDENTIFY ATTRACTIVE DRUG TARGETS INLISTERIA MONOCYTOGENESListeria monocytogenes (Lm) is a foodborne pathogen responsible for listeriosis in humans. Recently, Lm has developed resistances to a broad range of antimicrobials, including those used as the first choice of therapy. Moreover, multidrug-resistant strains have been detected in clinical isolates and food processing environments. This punctuates the need for novel antimicrobials against Lm. On the other hand, increasingly available omics data has created new opportunities for rational drug discovery. In this work, we generated multiple layers of omics data related to Lm, aiming to prioritize proteins that could serve as potential targets for antibiotic drug discovery. In order to determine the structural druggability of each protein encoded in Lm genome, experimental structures were retrieved from the Protein Data Bank (PDB). For all remaining proteins, we predicted their structure by homology modeling. Fpocket allowed the detection of protein cavities capable of interacting with drug-like compounds. Afterwards, Lm proteome was used as a query in BLASTp against human and microbiome proteins to avoid possible cross-interference. An essentiality analysis was also performed by looking for orthologs in DEG. The degree of conservation of each protein was determined by performing a multiple genome alignment of 25 Lm strains. Additionally, Lm metabolic network was built using Pathway Tools and analyzed as a reaction graph with Cytoscape, allowing the calculation of topological metrics. Finally, we included some previously published work that used microarrays analysis for gene expression from relevant conditions: intracellular replication in macrophages, intestinal lumen and blood. We combined this data in Target Pathogen in order to identify and prioritize attractive drug targets. Out of 2867 Lm proteins, we obtained 1925 structures. As expected, 98,5% of the structures modeled from a template co-crystallized with a drug-like compound were predicted as druggable. A total of 434 essential, druggable proteins with no close homologs in the human genome were kept. Afterward, we ranked these proteins according to a scoring function which takes into account the metabolic context, presence/absence in Lm strains, and upregulation during the infection-mimicking conditions. The best-ranked protein, transaldolase Tal2, participates in the Pentose Phosphate Pathway (PPP). The second one, rhamnulose-1-phosphate aldolase (RhaD), is implicated in the rhamnose utilization pathway. Other proteins in this pathway, such as rhamnulokinase (RhaB) and rhamnose mutarotase (RhaM) also harbor many features that make PPP an attractive target. We developed and applied an integrative analysis framework for the prioritization of protein targets in Lm. With our approach, pentose and rhamnose metabolism emerge as interesting potential targets for future drug development works.