Siderophores from pathogenic bacteria and bioactive peptides for the development of new antimicrobial andantitumor strategies

Abstract

Currently, the design and development of novel and efficient treatments against cancer and antimicrobial resistant infections is one of the major scientific challenges. In this context, this thesis dissertation aims to set the basis for the development of new antimicrobial and antitumor strategies based on the iron (III) uptake mechanisms employed by pathogenic bacteria, as well as the rational design of bioactive peptides. In chapter 1 the relevance of the siderophore-mediated iron uptake mechanisms utilized by pathogenic bacteria is discussed, highlighting their relevance in the development of novel antimicrobial strategies. Subsequently, the isolation and identification of the siderophores, along with the description of their associated genes, from four critical pathogens affecting humans (Acinetobacter baumannii) and fish from aquaculture (Vibrio neptunius, Tenacibaculum maritimum, and Vibrio anguillarum) are carefully described. The primary goal of these studies was to provide an extensive understanding of the virulence factors associated with these bacteria and to delineate potential novel therapeutic targets. In Chapter 2 a comprehensive introduction about the main features of antimicrobial and cell-penetrating peptides and their promising role in the development of novel antimicrobial and antitumor therapies is provided. Subsequently, two research projects, conducted during a research stay at the University of Pennsylvania (UPenn), are detailed. These studies were focused on the rational design and biological evaluation of new antimicrobial peptides based on natural scaffolds found in various venoms. Finally, a collaborative study with Universiti Teknologi MARA (Malaysia) is discussed. In this study, a homing peptide was rationally modified to enhance its capacity to permeabilize the membrane of cancer cells and potentially introduce active cargoes through a Trojan horse strategy.