Combatting AMR: a molecular approach to the discovery of potent and non-toxic rhenium complexes active against C. albicans-MRSA co-infection

Abstract

Antimicrobial resistance (AMR) is a major emerging threat to public health, causing serious issues in the successful prevention and treatment of persistent diseases. While the problem escalates, lack of financial incentive has lead major pharmaceutical companies to interrupt their antibiotic drug discovery programs. The World Health Organisation (WHO) has called for novel solutions outside the traditional development pathway, with emphasis on new classes of active compounds with nonclassical mechanisms of action. Metal complexes are an untapped source of antibiotic potential owing to unique modes of action and a wider range of three-dimensional geometries as compared to purely organic compounds. In this study, we present the antimicrobial and antifungal efficacy of a family of rhenium tricarbonyl diimine complexes with varying ligands, charge and lipophilicity. Our study allowed the identification of potent and non-toxic complexes active in vivo against S. aureus infections at MIC doses as low as 300 ng/mL, as well as against C. albicans-MRSA mixed co-infection. The compounds are capable of suppressing the C. albicans morphogenetic yeast-to-hyphal transition, eradicating fungal-S. aureus co-infection, while showing no sign of cardio-, hepato-, hematotoxiciy or teratogenicity.The following ALERTS were generated. Each ALERT has the format test-name_ALERT_alert-type_alert-level. Click on the hyperlinks for more details of the test.

Efficient direct nitrosylation of a-diimine rhenium tricarbonyl complexes to structurally nearly identical higher charge congeners activable towards photo-CO release

“…We recently reported studies on the antimicrobial properties of families of rhenium diimine (N-N) complexes and found several complexes of general formula fac-[Re I (CO) 3 (N-N)L] + (L = pyridine, py, type-ligand), showing low to no toxicity in vivo and potent in vitro and in vivo activity against infection of clinically relevant bacteria (MRSA) and fungi (Candida species). 19,20 Unlike similar complexes tested against cancers, where the overall charge of the compound does not seem to be a critical factor, a survey of the literature, and our own data, 20 indicates that positively charged rhenium complexes are most effective against the microbes. The mechanism of action these agents remains largely unknown, but we hypothesize that the positive charge of the complexes is important for their interaction with phosphatidylglycerol and cardiolipin anionic lipids.…”

Efficient Direct Nitrosylation of α-Diimine Rhenium Tricarbonyl Complexes to Structurally Nearly Identical Higher Charge Congeners Activable towards Photo-CO Release

“…As mentioned in the introduction, this study was initiated aiming at the synthesis of structurally nearly identical higher charge congeners of active antimicrobial rhenium tricarbonyl complexes. Our previous reports on those species indicate that neutral fac-[Re(CO) 3 (N-N)Br] bromo complexes are inactive, whereas several cationic complexes of general formula fac-[Re(CO) 3 (N-N)L] + (L = pyridine, py, type-ligand) show potent in vitro and in vivo activity against infection of clinically relevant bacteria (MRSA) and fungi (Candida species) [19,20]. We did not succeed in isolating stable fac-[Re(CO) 2 (NO)(N-N)L] 2+ species, but we decided to test the antimicrobial properties of the corresponding monocationic nitrosyl complexes fac-[Re(CO) 2 (NO)(N-N)X] + (1-4 and 12, where X = Br or BF 4 ).…”