Designing novel thiosemicarbazone Cu(I) complexes against gram positive methicillin susceptible Staphylococcus aureus and methicillin resistant Staphylococcus aureus

Abstract

Bacteria are microscopic, single cell organisms that can exist anywhere on earth. There are good bacteria that live synergistically inside the human body. Due to the disequilibrium in their proliferation and rapid transmission among hosts, they can be pathogenic to hosts. Misadministration of antibiotics directly assists bacteria to become multidrug resistant. Methicillin resistant Staphylococcus aureus (MRSA), gram positive multidrug resistant pathogenic bacteria, are categorized into the “serious” threat category, according to the CDC, and can cause major skin infections or even death. In response to the growing need for new antibiotics, it is worth uncovering the host-derived antibacterial immune response. Copper’s antibacterial characteristics have attracted interest from many research groups because they tend to show promising host-derived bactericidal effects. Cu(I) ions show more prominent antibacterial properties than Cu(II) ions via the formation of hydroxy radicals and displacement of Fe from Fe-S cluster proteins. During bacterial infections, activated macrophages increase the intake of Cu(I) ions through elevated expression of the copper importer, CTR1. Trafficking of Cu(I) ions into activated macrophages involves copper importers CTR1, chaperones ATX1, CCC2 and ATP7A- copper-transporting ATPases. Similarly, bacteria activate the copper chaperone CopZ to deliver excess Cu(I) ions to CopA and CopB efflux pumps in order to resist the bactericidal activity of Cu(I) ions. All these copper trafficking proteins consist of common metal binding domain “MXCXXC”. In this thesis, novel organic ligands for Cu(I) complexes are being explored for the treatment of multi drug resistant gram positive bacteria, such as Staphylococcus aureus. Thiosemicarbazones are promising candidates for complexation with Cu(I) and it has been demonstrated that the complexation of thiosemicarbazone with Cu(I) can enhance its antibacterial properties. In this research, extended versions of thiourea or thiosemicarbazone derivatives (abbreviated as NNSN) were the main focus in order to study the structure activity relationship against MSSA and MRSA. At initial stages, NNSN derivatives contained different substituted pyrazoles and 4-chlorophenyl groups. Based on the results, the substitution of electron donating groups at pyrazole’s 3C enhanced the antibacterial activity. Having amine, methyl and benzyl ether groups at 3C increased activity against MSSA and MRSA. However, the anti-bacterial activity of amine substituted NNSN compounds was diminished due to the structural isomerization. EDG substitution at 4C did not contribute to the antibacterial activity as those derivatives showed less activity in vitro. To date, the results proved that EDG substitution at 3C of the pyrazole ring and the thionyl center enhanced the copper dependent antibacterial properties of our NNSN candidates.