Ciprofloxacin metal complexes and linked dimers as potential antimicrobial agents

Antimicrobial resistance is one of the biggest threats to public health globally. Modifications to ciprofloxacin, a commercially available fluoroquinolone antibiotic, could overcome increasing antimicrobial resistance and increase its antimicrobial activity. Ciprofloxacin contains several potential donor atoms, which can be used to coordinate to a metal ion. Coordination of ciprofloxacin to bioavailable metal ions such as iron(III) could promote bacterial uptake of the metallo-ciprofloxacin complex, making it a more effective antimicrobial agent over ciprofloxacin. The coordination of ciprofloxacin to metal ions with antimicrobial properties such as bismuth(III) could also further enhance the antimicrobial properties. Presented are two novel iron(III)-ciprofloxacin complexes, a novel zinc(II)- ciprofloxacin complex and a bismuth(III)-ciprofloxacin complex. The metallo-ciprofloxacin complexes presented have been characterised using a variety of techniques, including X-ray crystallography, X-ray fluorescence (XRF), fourier-transform infrared spectroscopy (FTIR), elemental analysis, solid state nuclear magnetic resonance (ssNMR) and melting point. Another modification that can be made to the structure of ciprofloxacin is to design and synthesise a linked dimers. A dimeric compound could bridge across the binding sites of the intracellular target enzyme, DNA gyrase. Previously reported fluoroquinolone dimers have been found to possess enhanced antimicrobial properties as well as anti-tumour properties. Presented are two ciprofloxacin dimers, the first featuring an ethylenediaminetetraacetic acid (EDTA) linker and the second a diethylenetriamine pentaacetate (DTPA) linker. The EDTA and DTPA linkers have also been suggested to have antimicrobial properties due to their metal�chelating properties and therefore could further enhance the effectiveness of the ciprofloxacin dimers presented. The linked ciprofloxacin ligands presented have been characterised using nuclear magnetic resonance (NMR), High-performance liquid chromatography (HPLC), FTIR, elemental analysis and melting point

Mapping the Initial Stages of a Protective Pathway that Enhances Catalytic Turnover by a Lytic Polysaccharide Monooxygenase

Oxygenase and peroxygenase enzymes generate intermediates at their active sites which effect the controlled function-alization of inert C–H bonds in substrates, such as in the enzymatic conversion of methane to methanol. To be viable catalysts however, these enzymes must also prevent oxidative damage to essential active site residues, which can occur during both coupled and uncoupled turnover. Herein we use a combination of stopped-flow spectroscopy, targeted mu-tagenesis, TD-DFT calculations, high-energy resolution fluorescence detection X-ray absorption spectroscopy (HERFD-XAS), and electron paramagnetic resonance spectroscopy (EPR) to study two transient intermediates that together form a protective pathway built into the active sites of copper-dependent lytic polysaccharide monooxygenas-es (LPMOs). First, a transient high-valent species is generated at the copper histidine brace active site following treat-ment of the LPMO with either hydrogen peroxide or peroxyacids in the absence of substrate. This intermediate, which we propose to be a CuII-(histidyl radical), then reacts with a nearby tyrosine residue in an intersystem-crossing reac-tion to give a ferromagnetically coupled (S = 1) CuII-tyrosyl radical pair, thereby restoring the histidine brace active site to its resting state and allowing it to re-enter the catalytic cycle through reduction. This process gives the enzyme the capacity to minimize damage to the active site histidine residues ‘on the fly’ to increase total turnover number prior to enzyme deactivation, highlighting how oxidative enzymes are evolved to protect themselves from deleterious side reac-tions during uncoupled turnover