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.
Highlights
Among the many challenges to health, infectious diseases stand out for their ability to have a deep impact on humans and, have become a public health priority worldwide
The activity of 2 in combination with the antibiotics CST and CIP was evaluated by the microdilution two-dimensional checkerboard technique (Garcia and Isenberg, 2014)
We evaluated the effect over complex 2 antimicrobial activity of three major efflux pump inhibitors (EPIs): phenylalanine-arginine β-naphthylamide (PaβN), a broad-spectrum efflux inhibitor due to its behavior as a cationic peptide (Ughachukwu and Unekwe, 2012); carbonyl cyanide m-chlorophenyl-hydrazone (CCCP), which blocks proton-dependent electrochemical gradients (Park and Ko, 2015); and RSP, which inhibits mostly efflux systems of the resistance–nodulation-cell division family (Garvey and Piddock, 2008)
Summary
Among the many challenges to health, infectious diseases stand out for their ability to have a deep impact on humans and, have become a public health priority worldwide. The treatment of such infectious diseases remains a significant and global threat due to the emerging multidrug-resistant (MDR) or even pan-resistant pathogens refractory to virtually all clinically used antibiotics (Boucher et al, 2009). According to the Centers for Diseases Control and Prevention (CDC), 2.8 million antibiotic-resistant infections were reported in the United States in 2019, leading to more than 35,000 deaths (CDC, 2019). In February 2017, the World Health Organization (WHO) published a list of antibiotic-resistant priority pathogens that pose the greatest threat to human health. The panel of experts heartily recommended that future R + D strategies should be focused on the discovery and development of new antibiotics active against MDR Gram-negative bacteria (Shrivastava et al, 2018)
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