Synthesis and Structure–Activity Relationship Study of Antimicrobial Auranofin against ESKAPE Pathogens

Abstract

Auranofin, an FDA-approved arthritis drug, has recently been repurposed as a potential antimicrobial agent; it performed well against many Gram-positive bacteria, including multidrug resistant strains. It is, however, inactive toward Gram-negative bacteria, for which we are in dire need of new therapies. In this work, 40 auranofin analogues were synthesized by varying the structures of the thiol and phosphine ligands, and their activities were tested against ESKAPE pathogens. The study identified compounds that exhibited bacterial inhibition (MIC) and killing (MBC) activities up to 65 folds higher than that of auranofin, making them effective against Gram-negative pathogens. Both thiol and the phosphine structures influence the activities of the analogues. The trimethylphosphine and triethylphosphine ligands gave the highest activities against Gram-negative and Gram-positive bacteria, respectively. Our SAR study revealed that the thiol ligand is also very important, the structure of which can modulate the activities of the AuI complexes for both Gram-negative and Gram-positive bacteria. Moreover, these analogues had mammalian cell toxicities either similar to or lower than that of auranofin.

Synthesis, Antimicrobial Activity, Structure-Activity Relationship, and Molecular Docking Studies of Indole Diketopiperazine Alkaloids

“…Shi et al have reported that ferulic acid and ferulic acid alkyl esters (FAC2) with 1.4212 and 2.1762 of Clog P values showed higher antibacterial activity against E. coli as compared with other similar compounds having higher Clog P values (Shi et al, 2018). Moreover, this similar trend also was reported by Wu et al They found auranofin analogs with lower log P values (1–2) exhibited better activity than some analogs with higher log P values (>3) against S. aureus, E. coli , and P. aeruginosa (Wu et al, 2019). In view of the results, we can suggest that high hydrophobicity promotes reagents uptake by bacteria because of the lower Clog P value.…”

Metal Complexes, an Untapped Source of Antibiotic Potential?

“…The group of Yan prepared 40 auranofin analogues to determine their Gram(+), Gram(−), and cytotoxic activity, establishing a structure-activity relationship. Compounds (1-4) possessed a broader activity spectrum, with bactericidal activity against S. aureus, A. baumannii, Enterobacter cloacae, E faecium, and E. coli, with associated half maximal inhibitory concentration (IC 50 ) values between 50 and 100 µM against A549 cells (Table 1) [16]. For the Gram(+) bacteria tested, the cytotoxicity was around two orders of magnitude lower than the antibacterial activity, indicating a favorable therapeutic index.…”

“…As the longer chain length leads to more lipophilic compounds, the authors concluded that this increase in lipophilicity is responsible for the higher uptake [86]. Later studies showed that 10 16 preferentially binds RNA in live bacteria and accumulates at the ribosomes, condensing them when they form polysomes. This finding suggests that the compounds halt translation of RNA and thereby protein synthesis in bacteria [87].…”

“…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].…”

Glyco‐Conjugate Design and Demonstration as Receptors for the Species of Biological, Ecological and Medical Importance: Support from Spectroscopy and Microscopy

“…Auranofin is an anti‐arthritic drug and has been re‐purposed for antimicrobial activity. Auranofin showed activity against gram‐positive bacteria but had almost no effect against the gram‐negative ones [77] . To alter this, a number of auranofin analogues were generated by varying their thiol and phosphine functionalities and their antimicrobial activities were studied against ESKAPE pathogens (Figure 30).…”