Marina Cano,1 Enmanuel Cornielle,2 Alejandro Llamedo,1 Paula Pérez-Ramos,3 Pelayo A. Buelga,3 Humberto Rodríguez–Solla,3 Sara M. Soto,2,4 and Raquel G. Soengas3
1 Nalón Innova, Avenida de Galicia 31, 33005, Oviedo, Spain
2 ISGlobal, Hospital Clínic – Universitat de Barcelona, Barcelona, Spain
3 Departamento de Química Orgánica e Inorgánica, Instituto Universitario de Química Organometálica“Enrique Moles”, Universidad de Oviedo, Julián Clavería 8, 33006 Oviedo, Spain
4 CIBERINFEC, ISCIII – CIBER Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain
Antimicrobial resistance (AMR) has become one of the biggest global health challenges on the 21stcentury, demanding new strategies to restore antibiotic efficacy. Most of the antibiotics currently in clinical development are derivatives of already existing ones, which makes them susceptible to existing resistance mechanisms. In this context, the design of antibiotic drugs which include metal ions in their structure, the so-called metalloantibiotics have attracted much recent interest. Metal-based antibiotics offer significant advantages over purely organic drug candidates in the fight against AMR, but there are several potential limitations that must be overcome to reach clinical application. Metallodrugs usually display inadequate bioavailability, low accumulation at the therapeutic site and systemic toxicity. In this sense, recent studies describe encapsulation in nanotechnological systems as a general solution to overcome these problems, creating a protective environment for metallodrugsand drastically improving the efficacy and safety of the treatment.1
Our group has recently reported a new family of (C^S)-cyclometallated gold(III) complexes showing potent antibacterial activity.2 Belonging to this family, complex AuPyPZ display potent antimicrobial effects at clinically achievable concentrations but could have limited pharmacological interest due to its toxicity. However, upon encapsulation into liposomes, the resulting metalloantibiotic formulation not only shows high stability and suitable properties for drug delivery, but also a similar bactericidal action to that of the free drug and an increased cell viability.3
Another interesting feature of (C^S)-cyclometallated gold(III) metalloantibiotics is the excellent results obtained in vitro in combination therapy with aminoglycoside antibiotics, showing FICI values as low as 0.25 for multidrug resistant bacterial strains. Aiming at taking advantage of the observed synergic effects, we also developed a liposomal formulation that can co-deliver AuPyPZ metalloantibiotic and an aminoglycoside antibiotic such as gentamicin or amikacin. Antibacterial assays against multidrug-resistant S. aureus and S. epidermidis strains revealed that co-encapsulated formulations significantly reduced the MICs compared to free drugs or single-loaded liposomes. Proof of concept in MRSA model of skin infection validated the therapeutic potential of the liposomal formulation.