Microbial and plant prototypes as drug candidates for protozoan neglected diseases and multidrug-resistant bacteria

Abstract

Considering the advancement of the COVID-19 pandemic, the World Health Organization (WHO) has warned of its strong impact on vulnerable populations affected by neglected parasitic diseases and coinfections with SARS-CoV-2. The WHO also warned that due to the increase in hospital admissions, it became evident the need to expand the chemotherapy arsenal to fight multiresistant bacteria. Considering the therapeutic limitations in neglected protozooses, the significant increase in multidrug-resistant bacteria (ESKAPE), as well as the private sector's disregard for investing in new antibiotics, there is an urgent need for research into new drugs. Comprising a vast chemiodiversity, microbial and plant metabolites are one of the main sources of approved anti-infectious pharmaceutical prototypes. This project aims to identify new drug prototypes against Trypanosoma cruzi and Leishmania infantum, as well as for multiresistant "ESKAPE" bacteria, including Neisseria gonorrhoeae. Through the current project SPRINT FAPESP (2018 / 266557-7) with the University of Southampton (United Kingdom), partnerships with national universities (UFABC, USP, UNESP, UNIFESP), and international universities (University of Oxford -United Kingdom and Universität Münster -Germany), we will carry out an interdisciplinary project, using a well-established platform by the group, aiming at the study and selection of secondary metabolites of marine bacterial origin and compounds isolated from plants. Bacteria isolated from invertebrates and marine sediments will be identified by MALDI-TOF / MS and / or genetic sequencing. Using the OSMAC (One Strain Many Compounds) approach for the activation of cryptic genes, the differential production of secondary bacterial metabolites will be evaluated for antiparasitic / antimicrobial potential. Microbial active compounds, as well as plants, will be isolated through biomonitored studies using different separation and chromatographic techniques, supported by studies on nuclear magnetic resonance and LC-MS / MS (GNPS platform). The structural elucidation of active compounds will be carried out by spectrometric and spectroscopic techniques. Structural analogs based on natural bioactive compounds will be synthesized at Oxford, aiming at structure-activity studies. The compounds will be evaluated for potency (MIC / IC50) in microorganisms and toxicity in mammalian cells. Through in silico platforms, analyzes of the "drug-like" properties will be carried out, also eliminating interference compounds (PAINS). Studies of the antimicrobial and antiparasitic mechanisms of action will be carried out to evaluate changes in membranes, as well as bioenergetics and metabolic. Through an interdisciplinary and multicenter project, we intend to make available new prototypes for the synthesis of new therapeutic candidates, enabling pharmaceutical innovations for neglected parasitic diseases and multiresistant bacteria. (AU)