Phenazines as potential biomarkers of Pseudomonas aeruginosa infections: synthesis regulation, pathogenesis and analytical methods for their detection

Infectious diseases are still a worldwide important problem. This fact, has led to the characterization of new biomarkers that would allow an early, fast and reliable diagnostic and targeted therapy. In this context, Pseudomonas aeruginosa can be considered one of the most threatening pathogens since it causes a wide range of infections, mainly in patients that suffer other diseases. Antibiotic treatment is not trivial given the incidence of resistance processes and the fewer new antibiotics that are placed on the market. With this scenario, relevant quorum sensing (QS) molecules that regulate the secretion of virulence factors and biofilm formation can play an important role on diagnostic and therapeutic issues. In this review, we have focused our attention on phenazines, as possible new biomarkers. They are pigmented metabolites that are produced by diverse bacteria, characterized for presenting unique redox properties. Phenazines are involved on virulence, competitive fitness and are an essential component of the bacterial QS system. Here we describe their role on bacterial pathogenesis and we revise phenazine production regulation systems. We also discuss phenazine levels previously reported on bacterial isolates and on clinical samples to evaluate them as putative good candidates to be used as P. aeruginosa infection biomarkers. Moreover we deeply go through all analytical techniques that have been used for their detection and also new approaches are discussed from a critical point.This work has been funded by the Spanish government through the project QS4CF (RTI2018-096278-B-C21), by Fundació La Marató de TV3 (201825-30-31) and by the program Marie Sklodowska Research Fellowship through the project New Diagnostics for Infectious Diseases (ND4ID, 675412-ND4ID-H2020-MSCA-ITN-2015). The Nb4D group (formerly Applied Molecular Receptors group, AMRg) is a consolidated research group (Grup de Recerca) of the Generalitat de Catalunya and has support from the Departament d’Universitats, Recerca i Societat de la Informació de la Generalitat de Catalunya (expedient : 2014 SGR 1484). CIBER-BBN is an initiative funded by the Spanish National Plan for Scientific and Technical Research and Innovation 2013-2016, Iniciativa Ingenio 2010, Consolider Program, CIBER Actions are financed by the Instituto de Salud Carlos III with assistance from the European Regional Development Fund. The ICTS “NANBIOSIS”, and particularly the Custom Antibody Service (CAbS, IQAC-CSIC, CIBER-BBN), is acknowledged for the assistance and support related to some immunoreagents mentioned in this work.Peer reviewe