Gallium(III)-pyridoxal thiosemicarbazone derivatives as nontoxic agents against Gram-negative bacteria

Abstract

Many bacterial strains are developing mechanism of resistance to antibiotics, rendering last-resort antibiotics inactive. Therefore, new drugs are needed and in particular metal-based compounds represent a valid starting point to explore new antibiotic classes. In this study we have chosen to investigate gallium(III) complexes for their potential antimicrobial activity against different strains of Klebsiella pneumoniae, Escherichia coli and Pseudomonas aeruginosa which have developed different type of resistance mechanism, including the expression of β-lactamases (NDM-1, ESβL or AmpC) or the production of biofilm. We studied a series of thiosemicarbabazones derived from pyridoxal, their related Ga(III) complexes, and the speciation in solution of the Ga(III)/ligand systems as a function of the pH. Proton dissociation constants and conditional stability constants of Ga(III) complexes were evaluated by UV/Vis spectroscopy, and the most relevant species at physiological pH were identified. The compounds are active against resistant Gram negative strain with minimal inhibitory concentration in the μM range, while no cytotoxicity was detected in eukaryotic cells.

Design and Synthesis of Novel Antimicrobial Agents

“…Given its two essential functions in metabolism and iron acquisition, the E4PDH enzyme from A. baumannii may be critical in bacterial pathophysiology [ 128 ]. In addition to vitamin B6 derivatives, metals such as gold [ 130 ], nickel, copper [ 131 ] and gallium [ 132 ] are employed. Metal complexes were investigated for their potential antibiotic efficacy against various bacterial strains, and the results against resistant bacteria were encouraging.…”

A Semi‐Automated, High‐Throughput Approach for the Synthesis and Identification of Highly Photo‐Cytotoxic Iridium Complexes

“…While such workflows are being actively investigated for a large number of organic scaffolds and are a staple of structure-guided drug design, [13][14][15][16][17] to date there are very few studies where libraries of metal complexes are prepared and tested using such approaches. [18][19][20][21][22][23][24][25][26] Amongst these are those that have looked at the formation of ruthenium(II) arene Schiff-base and polypyridyl complexes and their subsequent mechanisms of initiating cell death, [18,20,23] including a recent investigation into the potential for machine learning to predict the properties of such complexes. [25] Previous studies have also explored combinatorial approaches with rhenium-(I) complexes to identify compounds with anticancer properties [19] and manganese(I) tricarbonyl complexes as potential antibacterial agents.…”

“…This is surprising, given that the modular assembly of ligands around a metal centre and often quantitative synthesis makes metal complexes ideally suited for the development of libraries of compounds via automated and high‐throughput workflows. While such workflows are being actively investigated for a large number of organic scaffolds and are a staple of structure‐guided drug design, [13–17] to date there are very few studies where libraries of metal complexes are prepared and tested using such approaches [18–26] . Amongst these are those that have looked at the formation of ruthenium(II) arene Schiff‐base and polypyridyl complexes and their subsequent mechanisms of initiating cell death, [18,20,23] including a recent investigation into the potential for machine learning to predict the properties of such complexes [25] .…”

“…Amongst these are those that have looked at the formation of ruthenium(II) arene Schiff‐base and polypyridyl complexes and their subsequent mechanisms of initiating cell death, [18,20,23] including a recent investigation into the potential for machine learning to predict the properties of such complexes [25] . Previous studies have also explored combinatorial approaches with rhenium(I) complexes to identify compounds with anticancer properties [19] and manganese(I) tricarbonyl complexes as potential antibacterial agents [26] …”

New Stable Gallium(III) and Indium(III) Complexes with Thiosemicarbazone Ligands: A Biological Evaluation

“…Biomedicinal uses of gallium are not new [ 1 ]: its applications spread from antitumor drugs [ 2 , 3 , 4 ], to antibiotics [ 5 , 6 , 7 ] and to radio imaging too [ 8 , 9 , 10 , 11 ]. Its activity takes place via different mechanisms depending on the application.…”