Antimicrobial efficacy of a hemilabile Pt(II)-NHC compound against drug-resistant S. aureus and Enterococcus

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)Cl-2] (3) were synthesized bearing pyridyl-functionalized butenyl-tethered (L1H) and n-butyl tethered ((LH)-H-2) 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 2.5x less dosage. An array of experiments reveals key characteristics for the hemilabile complex 1 as a potential anti-staphylococcal drug.