Cuomo, Paola (2022) Metabolomics as a means to control human bacterial infections using a Formyl peptide receptor antagonist. [Tesi di dottorato]

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Abstract

Helicobacter pylori (H. pylori) is a major human pathogen causing chronic infection, which generates a state of persistent inflammation, leading to severe gastric and extra-gastric outcomes. In the absence of effective vaccines, treatment of chronic H. pylori infection is the favorite approach for preventing the subsequent clinical implications. However, H. pylori eradication is a difficult clinical practice. Increasing antibiotic resistance, as well as the capacity of H. pylori to successfully evade the host immune system, make it a serious threat for human health. Consequently, novel pharmacological strategies are needed. The present PhD thesis focuses on the identification of new therapeutic agents for the management of H. pylori infection, modulating the host innate immune response, by targeting the Formyl peptide receptors (FPRs). FPRs participate to the host defense by orchestrating the inflammatory response. They have been widely recognized to play critical roles in inflammation-associated diseases. Thus, treatment with FPRs-modulation may be helpful to reduce H. pylori-associated inflammation and prevent the related clinical complications. Among FPRs, our attention was focused on FPR2, as the most attractive and promiscuous target. In this thesis the valorization of invasive marine biomasses for the production of natural anti-inflammatory agents, able to target FPRs, was investigated. Caulerpin, a bis-indole alkaloid isolated from algae of the genus Caulerpa, was identified as potential FPR2 inhibitor. By performing both in silico and in vitro studies, the efficacy of Caulerpin in modulating the immune response against H. pylori, by reverting the FPR2-related signaling cascade, was explored. Moreover, a holistic and omics approach, consisting in metabolomics analysis, was applied as a means useful to examine the role of Caulerpin in attenuating the H. pylori-induced inflammation and the related adverse clinical outcomes. This study might pave the way for a possible future use of Caulerpin as promising therapeutic or adjuvant anti-inflammatory agent against H. pylori infection.

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