A C∧S-Cyclometallated Gold(III) Complex as a Novel Antibacterial Candidate Against Drug-Resistant Bacteria

Abstract

The worldwide emergence and spread of infections caused by multidrug-resistant bacteria endangers the efficacy of current antibiotics in the clinical setting. The lack of new antibiotics in the pipeline points to the need of developing new strategies. Recently, gold-based drugs are being repurposed for antibacterial applications. Among them, gold(III) complexes have received increasing attention as metal-based anticancer agents. However, reports on their antibacterial activity are scarce due to stability issues. The present work demonstrates the antibacterial activity of the gold(III) complex 2 stabilized as C∧S-cycloaurated containing a diphenylphosphinothioic amide moiety, showing minimum inhibitory concentration (MIC) values that ranged from 4 to 8 and from 16 to 32 mg/L among Gram-positive and Gram-negative multidrug-resistant (MDR) pathogens, respectively. Complex 2 has a biofilm inhibitory activity of only two to four times than its MIC. We also describe for the first time a potent antibacterial synergistic effect of a gold(III) complex combined with colistin, showing a bactericidal effect in less than 2 h; confirming the role of the outer membrane as a permeability barrier. Complex 2 shows a low rate of internalization in Staphylococcus aureus and Acinetobacter baumannii; it does not interact with replication enzymes or efflux pumps, causes ultrastructural damages in both membrane and cytoplasmic levels, and permeabilizes the bacterial membrane. Unlike control antibiotics, complex 2 did not generate resistant mutants in 30-day sequential cultures. We detected lower cytotoxicity in a non-tumoral THLE-2 cell line (IC50 = 25.5 μM) and no acute toxicity signs in vivo after an i.v. 1-mg/kg dose. The characterization presented here reassures the potential of complex 2 as a new chemical class of antimicrobial agents.

Gold(III) Complexes Activity against Multidrug-Resistant Bacteria of Veterinary Significance

“…Previous studies on the antimicrobial activity of analogous gold(I) and gold(III) complexes showed a broad spectrum of antibacterial activities, and some even had a certain degree of selectivity towards Gram-positive species [ 27 ]. This trend is similar to that observed among clinical bacterial strains using the gold(III) complex 1 , presenting the lowest MIC values (8–16 mg/L) among the Gram-positive strains in contrast to Gram-negative strains (64 mg/L) [ 21 ]. Taking into account that Staphylococcus spp.…”

“…It should be noted that gold(III) dithiocarbamate complexes were more active against Gram-positive strains than the comparative antibiotics, ampicillin (except in the case of S. xylosus ) and vancomycin (VAN). In the case of Gram-negative species, and similar to what was observed with human strains [ 21 ], 1 did not show antibacterial activity, observing MIC values equal to 64 mg/L. Among the gold(III) complexes studied, 2f was the most active with MICs of 4–8 mg/L from all Gram-negative species including P. aeruginosa .…”

“…Among E. coli strains, 1 , 2a and 2d presented MBIC values lower than the corresponding MICs although only one to two-fold of difference. Complex 1 showed an MBIC of 16 mg/L that was lower than those obtained among human clinical strains [ 21 ]. In the case of 2b , 2e and 2f , MBIC values were very similar to the MIC among E. coli and S. panama strains.…”

“…We previously developed a novel (S^C)-cyclometallated gold(III) complex 1 based on an ortho -substituted phosphinothioic amide [ 20 , 21 ]. The interesting antibacterial profile of complex 1 prompted additional studies.…”

Gold-Derived Molecules as New Antimicrobial Agents

“…Accordingly, the biodistribution of gold antibiotics may be improved by inclusion in cyclodextrins ( Morgen et al, 2019 ; Tomasello et al, 2021 ). Recent studies have also described a potent synergistic microbicidal effect with antibiotics, suggesting that gold compounds may have great application prospects in combination therapy, potentiating the efficacy of clinically used antibiotics ( Ratia et al, 2022 ).…”