Investigation of metabolic alterations in ESKAPE microorganisms and infected patients using metabolomic approaches, and the discovery of bioactives from endophytic fungi for the prevention of nosocomial infections

• Grant number: 24/18638-6
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: November 01, 2024
• End date: October 31, 2026
• Field of knowledge: Biological Sciences - Microbiology - Biology and Physiology of Microorganisms
• Principal Investigator: Sergio Schenkman
• Grantee: Simone dos Santos Grecco
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated research grant: 21/10599-3 - The Antimicrobial Resistance Institute of São Paulo (The Aries Project), AP.CEPID

Abstract

According to the World Health Organization (WHO), antimicrobial resistance (AMR) is considered one of the world's greatest public health problems. It is mainly caused by the disorderly use of antimicrobial agents, leading to the death of millions of people annually and generating great economic losses for public organizations. Therefore, effective prevention and treatment strategies are urgently needed. A group of bacteria that has enormous potential for drug resistance mechanisms is the so-called "ESKAPE", composed of gram-negative and positive bacteria, which are the main causes of nosocomial infections. Given this scenario, understanding the molecular mechanisms involved in the adaptation of "ESKAPE" microorganisms that lead to AMR is considered one of the strategies for the development of new treatments. Omics analyses (genomics, transcriptomics, proteomics and metabolomics) combined with bioinformatics reveal the mechanism of adaptation of microorganisms and their relationship with AMR. Furthermore, they allow the investigation of samples from infected patients, aiming at the identification of metabolites that can be used as specific markers for microbial infections, and consequently the development of rapid diagnostic methods, allowing early and assertive treatment. Natural products are considered an important source of bioactive metabolites, due to their enormous chemodiversity. The presence of several compounds in the same extract gives natural products a great advantage, as they can act in synergy through different mechanisms of action, increasing efficacy with less chance of leading to AMR. When considering natural products with antimicrobial activities, extracts of fungal metabolism stand out, such as penicillin, obtained from strains of fungi of the genus Penicillium. The metabolic understanding of fungi, using bioinformatics and analytical chemistry tools, combined with antimicrobial activity tests, allows the discovery of new bioactive metabolites. Therefore, metabolomic techniques, in addition to elucidating important mechanisms in the adaptation of microorganisms to antimicrobial agents and allowing the identification of biomarkers that aid in the rapid diagnosis of bacterial infections, are also important tools in the discovery of new bioactives, in the prevention and treatment of nosocomial infections caused by "ESKAPE" microorganisms. Therefore, through this project, we propose to analyze the metabolism of "ESKAPE" bacteria prevalent in nosocomial infections, and to identify alterations, at the metabolic level, that indicate their adaptations and generation of resistance to antimicrobial agents. Analyze samples from patients affected by bacterial infections, especially by "ESKAPE" microorganisms, and identify important biomarkers for the future development of diagnostics through metabolomic approaches. Finally, to analyze bioactive extracts of endophytic fungi from the Brazilian Atlantic Forest using metabolomics combined with biological assays, aiming to map bioactive clusters and consequently potential metabolites for the prevention of nosocomial infections by "ESKAPE" microorganisms.