Copper intoxication inhibits aerobic nucleotide synthesis in Streptococcus pneumoniae

Johnson, Michael D. L.; Kehl-Fie, Thomas E.; Rosch, Jason W.

doi:10.1039/c5mt00011d

Cited by 53 publications

(68 citation statements)

References 54 publications

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“…Macomber and Imlay were the first to change the paradigm, delivering compelling evidence that, at least in Escherichia coli, the primary targets of copper toxicity are solvent-exposed iron-sulfur clusters of branched-chain amino acid synthesis dehydrogenases, not DNA (67). The actual target may also shift, though, depending upon the physiology of the organism in question; copper toxicity has been reported against an array of aerobic and anaerobic metabolic targets containing or constructing ironsulfur clusters (67)(68)(69)(70). Given the different metabolic targets in these different systems, it seems possible that copper, with its broad chemical effects and ligand affinities, may actually target a wide variety of metabolic pathways.…”

Section: Discussionmentioning

confidence: 99%

Disulfiram and Copper Ions Kill Mycobacterium tuberculosis in a Synergistic Manner

Dalecki

Haeili

Shah

et al. 2015

Antimicrob Agents Chemother

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Section: Discussionmentioning

confidence: 99%

Disulfiram and Copper Ions Kill Mycobacterium tuberculosis in a Synergistic Manner

Dalecki

Haeili

Shah

et al. 2015

Antimicrob Agents Chemother

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“…With a reported consensus binding sequence of KACAnnTGTA on the leading strand, we hypothesized that CopY may also bind other similar sequences as previously seen in Lactococcus lactis (48). Allowing for one base variation from the reported binding sequence, we found matches upstream of genes upregulated under copper stress and hypothesized that they may also be regulated by CopY (11, 49). Seven potential binding sites were assessed using BLI.…”

Section: Resultsmentioning

confidence: 95%

“…Multiple studies regarding the cop operon have been performed in S . pneumoniae (11, 17, 27, 32, 33, 35, 36). The pneumococcal cop operon contains, copY as the repressor, cupA as a membrane-associated copper chaperone, and copA as the copper-specific exporter (16, 27, 32).…”

Section: Introductionmentioning

confidence: 99%

Characterization of consensus operator site for Streptococcus pneumoniae copper repressor, CopY

O’Brien

Alvin

Menghani

et al. 2019

Preprint

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Copper is broadly toxic to bacteria. As such, bacteria have evolved specialized copper export systems (cop operons) often consisting of a DNA-binding/copper-responsive regulator (which can be a repressor or activator), a copper chaperone, and a copper exporter. For those bacteria using DNA-binding copper repressors, few studies have examined the regulation of this operon regarding the operator DNA sequence needed for repression. In Streptococcus pneumoniae (the pneumococcus), CopY is the copper repressor for the cop operon. Previously, these homologs have been characterized to bind a 10-base consensus sequence T/GACAnnTGTA. Here, we bioinformatically and empirically characterize these operator sites across species using S. pneumoniae CopY as a guide for binding. By examining the 21-base repeat operators for the pneumococcal cop operon and comparing binding of recombinant CopY to this, and the operator sites found in Enterococcus hirae, we show using biolayer interferometry that the T/GACAnnTGTA sequence is essential to binding, but it is not sufficient. We determine a more comprehensive S. pneumoniae CopY operator sequence to be RnYKACAAATGTARnY (where “R” is purine, “Y” is pyrimidine, and “K” is either G or T) binding with an affinity of 28 nM. We further propose that the cop operon operator consensus site of pneumococcal homologs be RnYKACAnnYGTARnY. This study illustrates the necessity to explore bacterial operator sites further to better understand bacterial gene regulation.

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“…Many bacteria have had specific targets identified ( e.g. , dehydratases in E. coli 43 , aerobic nucleotide synthesis in Streptococcus pneumoniae 44 , and heme biosynthesis in Neisseria gonorrhoeae 45 ), but outside of general mechanisms such as attacking iron-sulfur clusters in proteins, specific points of failure vary widely from organism to organism. The detected source of toxicity is simply the “weakest link,” or first component to fail.…”

Section: Discussionmentioning

confidence: 99%

Combinatorial phenotypic screen uncovers unrecognized family of extended thiourea inhibitors with copper-dependent anti-staphylococcal activity

et al. 2016

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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.

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Copper intoxication inhibits aerobic nucleotide synthesis in Streptococcus pneumoniae

Cited by 53 publications

References 54 publications

Disulfiram and Copper Ions Kill Mycobacterium tuberculosis in a Synergistic Manner

Disulfiram and Copper Ions Kill Mycobacterium tuberculosis in a Synergistic Manner

Characterization of consensus operator site for Streptococcus pneumoniae copper repressor, CopY

Combinatorial phenotypic screen uncovers unrecognized family of extended thiourea inhibitors with copper-dependent anti-staphylococcal activity

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