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

• Published in: Frontiers in microbiology Vol. 13; p. 815622
• Main Authors: Ratia, Carlos, Cepas, Virginio, Soengas, Raquel, Navarro, Yolanda, Velasco-de Andrés, María, Iglesias, María José, Lozano, Francisco, López-Ortiz, Fernando, Soto, Sara M
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 03-03-2022
• Subjects: cycloaurate; gold(III) antimicrobial; MDR; Microbiology; MRSA; synergy; cycloaurate; MDR; synergy; MRSA; gold(III) antimicrobial
• ISSN: 1664-302X; 1664-302X
• DOI: 10.3389/fmicb.2022.815622

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
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
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
shows a low rate of internalization in
and
; 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
did not generate resistant mutants in 30-day sequential cultures. We detected lower cytotoxicity in a non-tumoral THLE-2 cell line (IC
= 25.5 μM) and no acute toxicity signs
after an i.v. 1-mg/kg dose. The characterization presented here reassures the potential of complex
as a new chemical class of antimicrobial agents.