Abstract
The continuous rise of multi-drug resistant pathogenic bacteria has become a significant challenge for the health care system. In particular, novel drugs to treat infections of methicillin-resistant Staphylococcus aureus strains (MRSA) are needed, but traditional drug discovery campaigns have largely failed to deliver clinically suitable antibiotics. More than simply new drugs, new drug discovery approaches are needed to combat bacterial resistance. The recently described phenomenon of copper-dependent inhibitors has galvanized research exploring the use of metal-coordinating molecules to harness copper's natural antibacterial properties for therapeutic purposes. Here, we describe the results of the first concerted screening effort to identify copper-dependent inhibitors of Staphylococcus aureus. A standard library of 10 000 compounds was assayed for anti-staphylococcal activity, with hits defined as those compounds with a strict copper-dependent inhibitory activity. A total of 53 copper-dependent hit molecules were uncovered, similar to the copper independent hit rate of a traditionally executed campaign conducted in parallel on the same library. Most prominent was a hit family with an extended thiourea core structure, termed the NNSN motif. This motif resulted in copper-dependent and copper-specific S. aureus inhibition, while simultaneously being well tolerated by eukaryotic cells. Importantly, we could demonstrate that copper binding by the NNSN motif is highly unusual and likely responsible for the promising biological qualities of these compounds. A subsequent chemoinformatic meta-analysis of the ChEMBL chemical database confirmed the NNSNs as an unrecognized staphylococcal inhibitor, despite the family's presence in many chemical screening libraries. Thus, our copper-biased screen has proven able to discover inhibitors within previously screened libraries, offering a mechanism to reinvigorate exhausted molecular collections.
Highlights
Of the sixteen antibiotic classes used clinically, all but two were derived from environmental sources, and there is growing interest in returning to natural inspirations.[1,4,5,6] Among these inspirations lies metal-mediated innate immunity, by which the innate immune system directly modulates environmental levels of metals such as manganese, iron, zinc, and copper at the site of infection.[7,8] Through limitation, in the case of iron, zinc, and manganese or oversaturation, in the case of copper, the intrinsic properties of these ions are utilized to form a crucial line of defense against pathogens
Inspired by the innate immune system’s utilization of copper ions at sites of infection, we developed and deployed an improved high throughput screening (HTS) platform to search for small molecules with unique copper-dependent antimicrobial properties
(1) Nearly twice as many hits discovered through copperbiased screen as in a traditional screen
Summary
Of the sixteen antibiotic classes used clinically, all but two were derived from environmental sources, and there is growing interest in returning to natural inspirations.[1,4,5,6] Among these inspirations lies metal-mediated innate immunity, by which the innate immune system directly modulates environmental levels of metals such as manganese, iron, zinc, and copper at the site of infection.[7,8] Through limitation, in the case of iron, zinc, and manganese or oversaturation, in the case of copper, the intrinsic properties of these ions are utilized to form a crucial line of defense against pathogens. In many systems, including Mycobacterium tuberculosis, Pseudomonas aeruginosa, Listeria monocytogenes, and Streptococcus pneumoniae, bacterial copper resistance is linked to virulence;[9] attenuation of the ‘‘copper burst’’ within macrophages weakens the phagocytic response, promoting bacterial survival.[10,11] All sequenced bacteria possess at least a rudimentary level of copper resistance machinery,[12] varying from simple expression of an efflux pump,[13]
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