Antimicrobial efficacy of a hemilabile Pt(ii)–NHC compound against drug-resistant S. aureus and Enterococcus. Issue 7 (17th January 2023)

• Record Type: Journal Article
• Authors: Kaur, Mandeep; Thakare, Ritesh; Bhattacherya, Arindom; Murugan, Prem Anand; Kaul, Grace; Shukla, Manjulika; Singh, Alok Kr.; Matheshwaran, Saravanan; Chopra, Sidharth; Bera, Jitendra K.
• Is Part Of: Dalton transactions. Volume 52:Issue 7(2023)
• Page Start: 1876
• Page End: 1884
• Publication Date: 2023-01-17
• Subjects: Chemistry, Inorganic -- Periodicals; Chemistry, Physical and theoretical -- Periodicals; Chemistry, Inorganic -- Periodicals; 546.05
• DOI: 10.1039/d2dt03365h
• Languages: English
• ISSNs: 1477-9226

Abstract

Abstract : A newly designed Pt(ii )–NHC complex shows potent activity against the Gram-positive S. aureus pathogen. Further investigation reveals biofilm inhibition, in vivo activity inside mammalian cells, and combinatorial antimicrobial activity with FDA-approved drugs. Abstract : Three platinum(ii )–N-heterocyclic carbene (NHC) compounds [Pt(L 1 )Cl](PF6 ) (1 ), [Pt(L 2 )(COD)](PF6 )2 (2 ) and [Pt(L 2 )Cl2 ] (3 ) were synthesized bearing pyridyl-functionalized butenyl-tethered (L 1 H) and n -butyl tethered (L 2 H) NHC ligands, and their antibacterial activity against clinically relevant human pathogens was evaluated. Complex 1 was designed to have one of its metal coordination sites masked with a hemilabile butenyl group. The antibacterial activity spectrum against the ESKAPE panel of pathogens shows superior activity of 1 compared to 2 and 3 against the Gram-positive S. aureus pathogen. Complex 1 showed equipotent activity against clinical drug-resistant S. aureus and Enterococcus isolates. Furthermore, 1 demonstrated concentration-dependent bactericidal activity with a long post-antibiotic effect, eradicated preformed S. aureus biofilm and synergized with gentamicin and minocycline for combinatorial antimicrobial therapy. Under in vivo conditions, 1 displayed potent activity in reducing bacterial load in a murine thigh infection model, similar to vancomycin, albeit at 2.5× less dosage. An array of experiments reveals key characteristics for the hemilabile complex 1 as a potential anti-staphylococcal drug.