Drug Repurposing as a Strategy to Uncover Effective Antibacterial Compounds using Salmonella as a model

Abstract

Without doubt, antimicrobial resistance (AMR) is one of the most serious global challenge for public, animals and environmental health. Tackling this huge issue that is threatening modern medicine, is an urgent priority to regulatory agencies such as the World Health Organization (WHO) and the Centre for Disease Control and Prevention (CDC). The gap in the discovery and development of new antibiotics has turned the attention to alternative approaches, such as the repurposing of already existing drugs. In this Thesis, two different families of compounds were assessed for their potential antimicrobial activity. In the first section of this thesis, the antibacterial potential of two zinc- and one cobalt- metallic compounds (TS262, TS265 and TS267), previously reported as having antitumor properties, was investigated against Gram -positive and negative bacteria. The three antitumor compounds had antimicrobial activity against the bacteria tested however, when tested against human cells had an impact on viability. The second section of this work focused on the mechanism(s) of action of the antipsychotic from the family of phenothiazines, Thioridazine (TZ), using Salmonella enterica serovar Typhimurium ATCC14028S as a bacterium model. TZ has been widely studied worldwide due to its attractive antimicrobial activity however, the full mechanism of action of this drug in bacteria hasn t been fully understood. The results initially obtained in this Chapter, revealed that TZ does not seem to have a specific bacterial target. However, when tested in vitro against Salmonella, the studies conducted provide new insight(s) into the mechanism of action highlighting its effect(s) on the bacterial membrane and consequently in the generation of energy. Expanding on the potential of TZ to treat Salmonella-infected macrophages, the last chapter of this Thesis focused on the effect that TZ has on these cells. It was observed that the drug was able to impact intracellular survival of Salmonella, reducing the numbers of internalised bacteria and enhancing the killing activity of the infected macrophage. Similar effect had been previously reported in studies conducted on M. tuberculosis and S. aureus infected macrophages. These pathogens adapt and live in an intracellular niche. Consequently, compounds capable of reaching the site of infection are of a huge importance to tackle AMR. Taken together, the results obtained are promising and open an avenue for further studies using these compounds that can lead to the development of effective antimicrobials. Therefore, drug repurposing shows promise as an alternative strategy to fight infections caused by multidrug-resistant bacteria.