Introduction
The Gram-positive bacterium Staphylococcus aureus has acquired resistance to major antibiotic classes, and new treatment options are urgently needed[1]. One promising source of new drugs are the metal ion-transporting ionophores, which elicit broad-spectrum antimicrobial activity against a wide range of bacterial pathogens[2]. Here, we have identified a novel zinc-ionophore, designated “722” which demonstrates anti-staphylococcal activity in vivo.
Methods
Minimum inhibitory concentration (MIC) testing of ionophores was undertaken in cation-adjusted Mueller-Hinton broth (CAMHB) and physiologically relevant, bicarbonate positive cell culture medium, Roswell Park Memorial Institute (RPMI). The lead candidate, 722, was assessed for toxicity in vitro through measurement of lactate-dehydrogenase release in the established human cell-line, Detroit-562. Using the ST8: methicillin-resistant S. aureus (MRSA) strain USA300, the in vivo efficacy of 722 was evaluated using murine models of systemic and lung infection.
Results
In CAMHB, 722 demonstrated appreciable antimicrobial activity (MIC ≤ 4 µg/ml) against tested strains of multidrug-resistant S. aureus. MIC values for 722 were further reduced in RPMI, suggesting that bicarbonate may potentiate 722 activity. In vitro toxicity studies demonstrated that 722 had a comparable toxicity profile to the safe-for-human-use ionophore, PBT2[3, 4]. During in vivo models of MRSA infection, 722 demonstrated therapeutic efficacy in a murine model of lung infection, but not during systemic infection.
Conclusion
These results highlight the numerous factors that affect the accuracy of in vitro susceptibility testing and subsequent prediction of in vivo antimicrobial efficacy. Collectively, these data suggest that 722 is a promising antimicrobial candidate for the treatment of staphylococcal pulmonary infection.
References