Abstract
Multi-drug resistant Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), has become a worldwide, major health care problem. While initially restricted to clinical settings, drug resistant S. aureus is now one of the key causative agents of community-acquired infections. We have previously demonstrated that copper dependent inhibitors (CDIs), a class of antibiotics that are only active in the presence of copper ions, are effective bactericidal agents against MRSA. A second-generation CDI, APT-6K, exerted bactericidal activity at nanomolar concentrations. At sub-bactericidal concentrations, it effectively synergized with ampicillin to reverse drug resistance in multiple MRSA strains. APT-6K had a favorable therapeutic index when tested on eukaryotic cells (TI: > 30) and, unlike some previously reported CDIs, did not affect mitochondrial activity. These results further establish inhibitors that are activated by the binding of transition metal ions as a promising class of antibiotics, and for the first time, describe their ability to reverse existing drug resistance against clinically relevant antibiotics.
Highlights
Multi-drug resistant Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), has become a worldwide, major health care problem
The green circle denotes the NNSN motif. (b) Activity of adamantyl-bearing pyrazolyl-thioureas (APT)-6K against S. aureus strain Newman in media supplemented with 50 μM copper (Cu), cobalt (Co), manganese (Mn), nickel (Ni), zinc (Zn), or iron (Fe). (c) APT-6K and Cu were titrated against each other in a microplate assay and bacterial growth of the S. aureus strain Newman was determined after 20 hours. (d) Culture samples from each condition of the microplate assay in (d) were transferred into drop assays to determine whether any observed growth inhibition in (d) had been bacteriostatic or bactericidal in nature
A sub-group of NNSN compounds, which we described as adamantyl-bearing pyrazolyl-thioureas (APT), were further investigated for their activity against S. aureus
Summary
Multi-drug resistant Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), has become a worldwide, major health care problem. Copper dependent inhibitors (CDIs) are a functionally new type of antibiotic gaining increased appreciation due to their ability to inhibit drug resistant bacteria such as S. aureus, Mycobacterium tuberculosis, Mycoplasma spp., and Neisseria gonorrheae[7,8,9,10,11,12,13]. These compounds utilize copper for their activities and include the FDA approved drug disulfiram and anti-cancer compounds like 8-hydroxyquinoline (8HQ)[7,9,13,14,15]. We demonstrate the ability of APT-6K to overcome pre-existing drug resistance in S. aureus and that APT-6K, at concentrations that exert no anti-bacterial effect, restored the activity of ampicillin in resistant MRSA isolates
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