Copper and Antibiotics

Dalecki, Alex G.; Crawford, Cameron L.; Wolschendorf, Frank

doi:10.1016/bs.ampbs.2017.01.007

Cited by 104 publications

(33 citation statements)

References 310 publications

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“…The role of copper in infectious disease is multifaceted, as the metal is not only an essential nutrient but potentially toxic. The dual essential and toxic aspects of copper at the host-pathogen interface have been well-documented (90), and there is reemerging interest in harnessing copper's toxicity in the development of antimicrobials, particularly in the use of coppercomplexing compounds and copper ionophores (69,91). Consistent with other studies (73,78,80), we show that the metallophore PZ can cause C. albicans toxicity through overload of copper and other metals.…”

Section: Inhibiting the Vulnerable Active Site Of Copper-only Sodssupporting

confidence: 88%

“…CX is in the same 8-hydroxyquinoline family as CQ (68). 8-Hydroxyquinoline derivatives are known to form a complex with Cu(II), providing a potential mechanism for activity against SOD5 (69). CP is a known antifungal that is a member of the hydroxamic acid class of inhibitors, whereby hydroximate can chelate enzyme-bound metal co-factors (70,71).…”

Section: Metal Chelators As Chemical Inhibitors Of Copper-only Sod5mentioning

confidence: 99%

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Exploiting the vulnerable active site of a copper-only superoxide dismutase to disrupt fungal pathogenesis

Robinett

Culbertson

Peterson

et al. 2019

Journal of Biological Chemistry

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Edited by F. Peter GuengerichCopper-only superoxide dismutases (SODs) represent a new class of SOD enzymes that are exclusively extracellular and unique to fungi and oomycetes. These SODs are essential for virulence of fungal pathogens in pulmonary and disseminated infections, and we show here an additional role for copper-only SODs in promoting survival of fungal biofilms. The opportunistic fungal pathogen Candida albicans expresses three copperonly SODs, and deletion of one of them, SOD5, eradicated candidal biofilms on venous catheters in a rodent model. Fungal copper-only SODs harbor an irregular active site that, unlike their Cu,Zn-SOD counterparts, contains a copper co-factor unusually open to solvent and lacks zinc for stabilizing copper binding, making fungal copper-only SODs highly vulnerable to metal chelators. We found that unlike mammalian Cu,Zn-SOD1, C. albicans SOD5 indeed rapidly loses its copper to metal chelators such as EDTA, and binding constants for Cu(II) predict that copper-only SOD5 has a much lower affinity for copper than does Cu,Zn-SOD1. We screened compounds with a variety of indications and identified several metal-binding compounds, including the ionophore pyrithione zinc (PZ), that effectively inhibit C. albicans SOD5 but not mammalian Cu,Zn-SOD1. We observed that PZ both acts as an ionophore that promotes uptake of toxic metals and inhibits copper-only SODs. The pros and cons of a vulnerable active site for copper-only SODs and the possible exploitation of this vulnerability in antifungal drug design are discussed.

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Section: Inhibiting the Vulnerable Active Site Of Copper-only Sodssupporting

confidence: 88%

Section: Metal Chelators As Chemical Inhibitors Of Copper-only Sod5mentioning

confidence: 99%

Exploiting the vulnerable active site of a copper-only superoxide dismutase to disrupt fungal pathogenesis

Robinett

Culbertson

Peterson

et al. 2019

Journal of Biological Chemistry

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“…Copper selective pressure has grown in step with environmental oxygenation levels that increase copper bioavailability ( 79 ). Contemporary selection for copper resistance determinants has also arisen from copper’s widespread current use as an antimicrobial agent ( 80 ). Assuming that the core Lgt-Lsp pathway was initially established in prokaryotes and that selective pressure for Lpp N -acylation arose after establishment of the various lineages, different bacterial species would have subsequently acquired N -acylation systems independently from each other.…”

Section: Discussionmentioning

confidence: 99%

Lipoprotein N -Acylation in Staphylococcus aureus Is Catalyzed by a Two-Component Acyl Transferase System

Gardiner

Komazin

Matsuo

et al. 2020

mBio

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Bacterial lipoproteins (Lpps) are a class of membrane-associated proteins universally distributed among all bacteria. A characteristic N-terminal cysteine residue that is variably acylated anchors C-terminal globular domains to the extracellular surface, where they serve numerous roles, including in the capture and transport of essential nutrients. Lpps are also ligands for the Toll-like receptor 2 (TLR2) family, a key component of the innate immune system tasked with bacterial recognition. While Lpp function is conserved in all prokaryotes, structural heterogeneity in the N-terminal acylation state is widespread among Firmicutes and can differ between otherwise closely related species. In this study, we identify a novel two-gene system that directs the synthesis of N-acylated Lpps in the commensal and opportunistic pathogen subset of staphylococci. The two genes, which we have named the lipoprotein N-acylation transferase system (Lns), bear no resemblance to previously characterized N-terminal Lpp tailoring enzymes. LnsA (SAOUHSC_00822) is an NlpC/P60 superfamily enzyme, whereas LnsB (SAOHSC_02761) has remote homology to the CAAX protease and bacteriocin-processing enzyme (CPBP) family. Both LnsA and LnsB are together necessary and alone sufficient for N-acylation in Staphylococcus aureus and convert the Lpp chemotype from diacyl to triacyl when heterologously expressed in Listeria monocytogenes. Acquisition of lnsAB decreases TLR2-mediated detection of S. aureus by nearly 10-fold and shifts the activated TLR2 complex from TLR2/6 to TLR2/1. LnsAB thus has a dual role in attenuating TLR2 signaling in addition to a broader role in bacterial cell envelope physiology. IMPORTANCE Although it has long been known that S. aureus forms triacylated Lpps, a lack of homologs to known N-acylation genes found in Gram-negative bacteria has until now precluded identification of the genes responsible for this Lpp modification. Here, we demonstrate N-terminal Lpp acylation and chemotype conversion to the tri-acylated state is directed by a unique acyl transferase system encoded by two noncontiguous staphylococci genes (lnsAB). Since triacylated Lpps stimulate TLR2 more weakly than their diacylated counterparts, Lpp N-acylation is an important TLR2 immunoevasion factor for determining tolerance or nontolerance in niches such as in the skin microbiota. The discovery of the LnsAB system expands the known diversity of Lpp biosynthesis pathways and acyl transfer biochemistry in bacteria, advances our understanding of Lpp structural heterogeneity, and helps differentiate commensal and noncommensal microbiota.

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“…Many studies attribute the antibacterial activity of copper to the capacity of the released ions to cause a great oxidative stress by producing reactive oxygen species in aerobic conditions. As a result, the first stage is a cell membrane degradation which allows copper ions to penetrate into the cell and damage lipids, proteins, nucleic acids and eventually to destroy the whole genetic material [ 21 ]. Destruction of genetic material is especially important in the context of growing drug resistance of bacteria causing hospital-acquired infections.…”

Section: Discussionmentioning

confidence: 99%

Antimicrobial effect of copper alloys on Acinetobacter species isolated from infections and hospital environment

Różańska

Chmielarczyk

Romaniszyn

et al. 2018

Antimicrob Resist Infect Control

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BackgroundAn increased proportion of Gram-negative bacteria have recently been reported among etiologic agents of infection. In Poland, Acinetobacter baumannii is a big problem for hospitals, especially intensive care units. Touch surfaces made from materials with antimicrobial properties, especially copper alloys, are recommended as a supplementary method of increasing biological safety in the hospital environment.Aim of the studyThe objective of this study is to determine the susceptibility to selected copper alloys of three clinical Acinetobacter baumannii strains, one Acinetobacter lwoffi and an A. pittii strain isolated from the hospital environment.Material and methodThe modification of the Japanese Standard, which the ISO 22196:2011 norm was used for testing antimicrobial properties of CuZn37, CuSn6 and CuNi18Zn20 and Cu-ETP and stainless steel as positive and negative control, respectively.ResultsThe highest cidal efficiency, expressed as both time and the degree of reduction of the initial suspension density, against all of the tested Acinetobacter strains was found for ETP copper. But, the results of our study also confirmed effective activity (bacteriocidal or bacteriostatic) of copper alloys selected for the study, contrary to the stainless steel. The reduction in bacterial suspension density is significantly different depending on the strain and copper alloy composition.ConslusionsThe results of our study confirmed the effective antibacterial activity of copper and its selected alloys against clinical Acinetobacter baumannii and Acinetobacter lwoffii strains, and Acinetobacter pittii strain isolated from the hospital environment.

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Copper and Antibiotics

Cited by 104 publications

References 310 publications

Exploiting the vulnerable active site of a copper-only superoxide dismutase to disrupt fungal pathogenesis

Exploiting the vulnerable active site of a copper-only superoxide dismutase to disrupt fungal pathogenesis

Lipoprotein N -Acylation in Staphylococcus aureus Is Catalyzed by a Two-Component Acyl Transferase System

Antimicrobial effect of copper alloys on Acinetobacter species isolated from infections and hospital environment

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