SYNTHESIS AND CHARACTERIZATION OF ANTIMICROBIAL DERIVATIVES

The synthesis of molecules with antimicrobial activity, and the characterization of active and non-active substances produced by bacteria, represents the central core of this doctoral dissertation. In particular, it has been possible to demonstrate both the versatility of 1,2,4oxadiazole and triazole derivatives in the field of antimicrobials drugs, and how the study of bacterial metabolites can be a source of inspiration for the characterization of molecules with active properties or bio-polymer extraction. Antimicrobial resistance (AMR) constitutes an important global public health and developmental issue. The improper use and excessive application of antimicrobials in humans, animals, and plants are the primary factors contributing to the emergence of drug-resistant pathogens. Antimicrobial resistance (AMR) impacts nations across all geographical regions and income brackets. Antimicrobial resistance jeopardizes numerous advancements in contemporary medicine. It complicates the treatment of infections and renders other medical procedures and treatments, such as surgery, caesarean sections, and cancer chemotherapy, significantly more perilous. In addition to death and injury, AMR carries considerable economic expenses. The World Bank estimates that AMR might result in US$ 1 trillion in increased healthcare expenses by 2050, as well as US$ 1 trillion to US$ 3.4 trillion in annual GDP losses by 2030. Priorities for addressing AMR in human health include preventing all infections that may result in inappropriate antimicrobial use; ensuring universal access to quality diagnosis and appropriate infection treatment; and strategic information and innovation, such as AMR surveillance and antimicrobial consumption/use, as well as research and development for novel vaccines, diagnostics, and medicines. Consequently, the increasing incidence of antibiotic resistance and the arrival of novel viral diseases, such as COVID-19 pandemic, render the identification of new compounds with antimicrobial properties essential. In this context, both organic chemistry and omics sciences are pivotal. The synthesis of novel molecules enables the modulation of the physicochemical and biological properties of compounds, allowing the development of more effective and selective pharmaceuticals. Meanwhile, the characterization of natural molecules derived from microorganisms is crucial for understanding and leveraging the interactions among them and the environment. The combination of novel synthetic methodologies with sophisticated analytical techniques provides robust instruments for the advancement of new antimicrobials, effectively tackling modern health issues. Beyond the development of novel antimicrobials, it is equally important to explore the broader potential of bacterial metabolites for both pharmaceutical and nonpharmaceutical applications. Microbial secondary metabolites represent a vast and largely untapped reservoir of bioactive compounds with therapeutic properties, including anti cancer, anti-inflammatory, and immunomodulatory activities. At the same time, bacteria can serve as sustainable biofactories to produce biomaterials and bioplastics, offering environmentally friendly alternatives to petrochemical-based products. Harnessing these metabolic pathways not only diversifies the pipeline of drug discovery but also contributes to circular bioeconomy strategies by reducing dependency on non-renewable resources. Thus, the valorization of bacterial metabolites extends far beyond combating antimicrobial resistance, positioning microbes as key players in both human health and sustainable industrial innovation. The first chapter is divided into 3 parts. The first one discusses the synthesis of 1,2,4-oxadiazole and 1,2,4-triazole derivatives linked with both mono- and bis-cationic pyridinium salts, studying their antibacterial properties, inhibition of resistant strains and biofilms. The second part of the chapter focuses on the synthesis of mono-cationic pyridinium salts with a central oxadiazole core and optimized physicochemical properties. Specifically, application studies of compounds with improved antibacterial characteristics have been performed, leading to glycerol-based gels and PVC-based films with antibacterial features. The third part of the chapter focuses on the synthesis of tripodal compounds with antiviral characteristics. Specifically, compounds designed to be active on Mpro of SARS-CoV-2 in response to COVID19 pathology. Through docking and induced fit docking studies on the target, it was possible to narrow the field to a set of oxadiazole derivatives that are synthesized in the last part of this chapter (Figure 1). Figure 1. Schematic representation of antimicrobial drug-discovery process, reported in Chapter I. The second chapter, on the other hand, focuses on the use of bacteria as “biofactories” of both antimicrobial compounds and biopolymers such as polyhydroxyalkanoates (PHAs). This chapter will be divided into 3 parts as well, the first and second parts are based on bacterial endophytes found in the Origanum Heracleoticum plant and bacteria found in the Gobi Desert soil respectively. Their ability to inhibit the growth of other pathogenic bacteria has been studied and the production of volatile organic compounds (VOCs) potentially responsible for antibacterial activity has been highlighted (Figure 2a). The third part, on the other hand, reports an alternative and green method to purify and extract PHA produced from bacterial biomass collected by a filtration system present at the University of Palermo (Figure 2b).