Auranofin and its Analogues Show Potent Antimicrobial Activity against Multidrug‐Resistant Pathogens: Structure–Activity Relationships

Marzo, Tiziano; Cirri, Damiano; Pollini, Simona; Prato, Marco; Fallani, Stefania; Cassetta, Maria Iris; Novelli, Andréa; Rossolini, Gian María; Messori, Luigi

doi:10.1002/cmdc.201800498

Cited by 54 publications

(44 citation statements)

References 36 publications

(41 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Other studies hypothesized that the outer membranes of Gram(−) species are able to prevent auranofin accumulation. This is supported by the finding that co-administration of auranofin with membrane permeabilizing antibiotics such as polymyxin B lead to restored activity against Gram(−) bacteria [44,45].…”

Section: Introductionmentioning

confidence: 80%

Metal Complexes, an Untapped Source of Antibiotic Potential?

2020

View full text Add to dashboard Cite

With the widespread rise of antimicrobial resistance, most traditional sources for new drug compounds have been explored intensively for new classes of antibiotics. Meanwhile, metal complexes have long had only a niche presence in the medicinal chemistry landscape, despite some compounds, such as the anticancer drug cisplatin, having had a profound impact and still being used extensively in cancer treatments today. Indeed, metal complexes have been largely ignored for antibiotic development. This is surprising as metal compounds have access to unique modes of action and exist in a wider range of three-dimensional geometries than purely organic compounds. These properties make them interesting starting points for the development of new drugs. In this perspective article, the encouraging work that has been done on antimicrobial metal complexes, mainly over the last decade, is highlighted. Promising metal complexes, their activity profiles, and possible modes of action are discussed and issues that remain to be addressed are emphasized.Antibiotics 2020, 9, 90 2 of 24 Metal-containing compounds have played a small but seminal role in medicinal chemistry of throughout the 20th century. An arsenic-containing compound, Salvarsan, was discovered at the beginning of the century and became the first effective treatment of syphilis [9]. It was however the discovery of the anticancer drug cisplatin and its successors that really kickstarted the field of inorganic medicinal chemistry. Even today, platinum-based chemotherapeutics are still used in the majority of cancer treatments [10]. The gold-containing auranofin is an approved drug for the treatment of rheumatoid arthritis and is currently under investigation for its anticancer as well as antimicrobial properties [11][12][13][14][15][16]. Invigorated by these breakthrough successes, the field has expanded to many other elements in the last few decades, with complexes of titanium, iron, ruthenium, gallium, palladium, silver, gold, bismuth, and copper entering clinical trials [17][18][19][20][21][22]. The medicinal applications of these metal complexes range from anticancer to antimalaria over to neurodegenerative diseases. Strangely, antibacterial applications are remarkably sparse in this list and the number of literature reports on metal-based antimicrobials is dwarfed by the much more frequent publications on metal-based anticancer compounds. This is surprising as metals such as bismuth and silver have long been known to possess antibacterial properties. Some medicinal products are currently available. There are however a variety of products, such as silver-coated underwear, with a more dubious scientific basis. Nevertheless, the systematic evaluation of the antimicrobial properties of metal complexes has increased in pace over the last decade, with several reports highlighting the activity and potential modes of action of metal-based antibiotics. This perspective article will discuss the major discoveries in the non-traditional field of metal complex-based antibiotic co...

show abstract

Section: Introductionmentioning

confidence: 80%

Metal Complexes, an Untapped Source of Antibiotic Potential?

2020

View full text Add to dashboard Cite

show abstract

“…Auranofin and Au(PEt 3 )Cl were purchased respectively from Enzo Life Sciences and Sigma-Aldrich and used without further purifications. The remaining complexes were prepared in our laboratory following already reported procedures [ 18 , 19 ]. All solvents and reagents used during metal complexes preparation were purchased from Sigma-Aldrich (Milan, Italy) and used without further purifications.…”

Section: Methodsmentioning

confidence: 99%

“…The investigational panel included auranofin and eight additional silver and gold complexes related to it ( Figure 1 ). The synthesis, characterization and solution behavior of these molecules were previously described [ 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

Antiproliferative Properties of a Few Auranofin-Related Gold(I) and Silver(I) Complexes in Leukemia Cells and their Interferences with the Ubiquitin Proteasome System

et al. 2020

Self Cite

View full text Add to dashboard Cite

A group of triethylphosphine gold(I) and silver(I) complexes, structurally related to auranofin, were prepared and investigated as potential anticancer drug candidates. The antiproliferative properties of these metal compounds were assessed against two leukemia cell lines, i.e., CCRF-CEM and its multidrug-resistant counterpart, CEM/ADR5000. Interestingly, potent cytotoxic effects were disclosed for both series of compounds against leukemia cells, with IC50 values generally falling in the low-micromolar range, the gold derivatives being on the whole more effective than the silver analogues. Some initial structure-function relationships were drawn. Subsequently, the ability of the study compounds to inhibit the three main catalytic activities of the proteasome was investigated. Different patterns of enzyme inhibition emerged for the various metal complexes. Notably, gold compounds were able to inhibit effectively both the trypsin-like and chymotrypsin-like proteasome activities, being less effective toward the caspase-like catalytic activity. In most cases, a significant selectivity of the study compounds toward the proteasome proteolytic activities was detected when compared to other proteases. The implications of the obtained results are discussed.

show abstract

“…The leading compound of this family of metallodrugs is auranofin (2,3,4,6-tetra-o-acetyl-L-thio-β-D-glyco-pyranosato-S-(triethyl-phosphine)-gold(I), Figure 1). It is clinically approved for the treatment of rheumatoid arthritis; however, in the frame of the so called "drug repositioning" strategy, in recent years, an extensive reappraisal of its medicinal properties was started unveiling its potential application as antibacterial (Cassetta et al, 2014;Thangamani et al, 2016;Marzo et al, 2018), antiviral (AbdelKhalek et al, 2019Marzo and Messori, 2020), antifungal, and antiparasitic agent (Bulman et al, 2015;Wiederhold et al, 2017). Moreover, the remarkable in vitro antiproliferative properties of this compound fueled the widespread studies of its antitumor activity.…”

Section: Introductionmentioning

confidence: 99%

Mechanistic Insights Into the Anticancer Properties of the Auranofin Analog Au(PEt3)I: A Theoretical and Experimental Study

et al. 2020

Self Cite

View full text Add to dashboard Cite

Au(PEt 3)I (AF-I hereafter), the iodide analog of the FDA-approved drug auranofin (AF hereafter), is a promising anticancer agent that produces its pharmacological effects through interaction with non-genomic targets such as the thioredoxin reductase system. AF-I is endowed with a very favorable biochemical profile showing potent in vitro cytotoxic activity against several cancer types including ovarian and colorectal cancer. Remarkably, in a recent publication, some of us reported that AF-I induces an almost complete and rapid remission in an orthotopic in vivo mouse model of ovarian cancer. The cytotoxic potency does not bring about highly severe side effects, making AF-I very well-tolerated even for higher doses, even more so than the pharmacologically active ones. All these promising features led us to expand our studies on the mechanistic aspects underlying the antitumor activity of AF-I. We report here on an integrated experimental and theoretical study on the reactivity of AF-I, in comparison with auranofin, toward relevant aminoacidic residues or their molecular models. Results point out that the replacement of the thiosugar moiety with iodide significantly affects the overall reactivity toward the amino acid residues histidine, cysteine, methionine, and selenocysteine. Altogether, the obtained results contribute to shed light into the enhanced antitumoral activity of AF-I compared with AF.

show abstract

Auranofin and its Analogues Show Potent Antimicrobial Activity against Multidrug‐Resistant Pathogens: Structure–Activity Relationships

Cited by 54 publications

References 36 publications

Metal Complexes, an Untapped Source of Antibiotic Potential?

Metal Complexes, an Untapped Source of Antibiotic Potential?

Antiproliferative Properties of a Few Auranofin-Related Gold(I) and Silver(I) Complexes in Leukemia Cells and their Interferences with the Ubiquitin Proteasome System

Mechanistic Insights Into the Anticancer Properties of the Auranofin Analog Au(PEt3)I: A Theoretical and Experimental Study

Contact Info

Product

Resources

About