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Multi-target mode of action of silver against Staphylococcus aureus endows it with capability to combat antibiotic resistance.

ABSTRACT: The rapid emergence of drug resistant Staphylococcus aureus (S. aureus) poses a serious threat to public health globally. Silver (Ag)-based antimicrobials are promising to combat antibiotic resistant S. aureus, yet their molecular targets are largely elusive. Herein, we separate and identify 38 authentic Ag⁺-binding proteins in S. aureus at the whole-cell scale. We then capture the molecular snapshot on the dynamic action of Ag⁺ against S. aureus and further validate that Ag⁺ could inhibit a key target 6-phosphogluconate dehydrogenase through binding to catalytic His185 by X-ray crystallography. Significantly, the multi-target mode of action of Ag⁺ (and nanosilver) endows its sustainable antimicrobial efficacy, leading to enhanced efficacy of conventional antibiotics and resensitization of MRSA to antibiotics. Our study resolves the long-standing question of the molecular targets of silver in S. aureus and offers insights into the sustainable bacterial susceptibility of silver, providing a potential approach for combating antimicrobial resistance.

SUBMITTER: Wang H

PROVIDER: S-EPMC8184742 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Dual Mode of Action for Plusbacin A3 in Staphylococcus aureus.

Project description:We have used C{F}, N{F}, and N{P} rotational-echo double resonance NMR to determine the location and conformation of 19F and 15N double-labeled plusbacin A3 and of double-labeled deslipo-plusbacin A3, each bound to the cell walls of whole cells of Staphyloccocus aureus grown in media containing [1-13C]glycine. The 31P is primarily in wall teichoic acid. Approximately 25% of plusbacin headgroups (the cyclic depsipeptide backbone) are in a closed conformation (N-F separation of 6 Å), while 75% are in a more open conformation (N-F separation of 12 Å). The closed headgroups have no contact with wall teichoic acid, whereas the open headgroups have a strong contact. This places the closed headgroups in hydrophobic regions of the cell wall and the open headgroups in hydrophilic regions. None of the plusbacin tails have contact with the 31P of either wall teichoic acid or the cell membrane and thus are in hydrophobic regions of the cell wall. In addition, both heads and tails of plusbacin A3 have contact with the glycyl 13C incorporated in cell-wall peptidoglycan pentaglycyl bridges and with 13C-labeled purines near the membrane surface. We interpret these results in terms of a dual mode of action for plusbacin A3: first, disruption of the peptidoglycan layer nearest to the membrane surface by closed-conformation plusbacin A3 leading to an inhibition of chain extension by transglycosylation; second, thinning and disruption of the membrane (possibly including disruption of ATP-binding cassette transporters embedded in the membrane) by open-conformation plusbacin A3, thereby leading to release of ATP to the hydrophilic regions of the cell wall and subsequent binding by plusbacin A3.

| S-EPMC5555578 | biostudies-literature

Mode of action analysis: Distinct Staphylococcus aureus transcriptome changes upon antivirulence lactone treatment

Project description:To elucidate the antivirulent lactone U1 mode of action, next generation sequencing was applied to analyze the transcriptome of NCTC 8325 cells treated with either compound or DMSO as control.

2018-01-01 | GSE79407 | GEO

Mode of action studies of the novel bisquaternary bisnaphthalimide MT02 against Staphylococcus aureus

Project description:Screening of various bisquaternary bisnaphthalimides against a variety of human pathogens revealed one compound, designated MT02, with strong inhibitory effects against gram-positive bacteria. The minimal inhibitory concentrations ranged from 0.31 µg/ml against community-acquired methicillin resistant Staphylococcus aureus (MRSA) strain USA300 to 20 µg/ml against Streptococcus pneumonia. DNA-microarray studies generated a transcriptional signature characterized by a strong increase of genes involved in DNA-metabolism, DNA-replication, SOS-response and transport of positively charged compounds. Radioactive whole cell labeling experiments indicated a strong impact of MT02 on bacterial DNA-replication. Furthermore, surface plasmon resonance and gel retardation experiments demonstrated direct binding of MT02 to DNA in a concentration dependent, reversible and sequence-unspecific manner. The data presented suggest that the bisquaternary bisnaphthalimide MT02 exerts anti-gram-positive activity by binding to DNA and thereby prohibiting appropriate DNA-replication.

2011-01-04 | GSE23077 | GEO

Mode of action studies of the novel bisquaternary bisnaphthalimide MT02 against Staphylococcus aureus

2011-01-04 | E-GEOD-23077 | biostudies-arrayexpress

Mode of action analysis: Distinct Staphylococcus aureus transcriptome changes upon antivirulence hydroxy amide treatment

Project description:To elucidate the antivirulent hydroxy amide (R*,R*)-3 mode of action, next generation sequencing was applied to analyze the transcriptome of NCTC 8325 cells treated with either compound or DMSO as control.

2016-01-14 | GSE64747 | GEO

Mode-of-action studies of the novel bisquaternary bisnaphthalimide MT02 against Staphylococcus aureus.

Project description:Screening of various bisquaternary bisnaphthalimides against a variety of human pathogens revealed one compound, designated MT02, with strong inhibitory effects against Gram-positive bacteria. The MICs ranged from 0.31 μg/ml against community-acquired methicillin-resistant Staphylococcus aureus (MRSA) lineage USA300 to 20 μg/ml against Streptococcus pneumoniae. Radioactive whole-cell labeling experiments indicated a strong impact of MT02 on bacterial DNA replication. DNA microarray studies generated a transcriptional signature characterized by stronger expression of genes involved in DNA metabolism, DNA replication, SOS response, and transport of positively charged compounds. Furthermore, surface plasmon resonance and gel retardation experiments demonstrated direct binding of MT02 to DNA in a concentration-dependent, reversible, and non-sequence-specific manner. The data presented suggest that the bisquaternary bisnaphthalimide MT02 exerts anti-Gram-positive activity by binding to DNA and thereby preventing appropriate DNA replication.

| S-EPMC3019648 | biostudies-literature

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Project description:Bacterial persister cells are phenotypic variants that exhibit a transient non-growing state and antibiotic tolerance. Here we provide in vitro evidence of Staphylococcus aureus persisters within infected host cells. We show that the bacteria surviving antibiotic treatment within host cells are persisters, displaying biphasic killing and reaching a uniformly non-responsive, non-dividing state when followed at the single-cell level. This phenotype is stable but reversible upon antibiotic removal. Intracellular S. aureus persisters remain metabolically active, but display an altered transcriptomic profile consistent with activation of stress responses, including the stringent response as well as cell-wall stress, SOS and heat-shock responses. These changes are associated with multidrug tolerance after exposure to a single antibiotic. We hypothesize that intracellular S. aureus persisters may constitute a reservoir for relapsing infection, and could contribute to therapeutic failures.

2020-03-25 | GSE139659 | GEO

Exploiting dominant-negative toxins to combat Staphylococcus aureus pathogenesis.

Project description:Staphylococcus aureus (S. aureus) is a human pathogen that relies on the subversion of host phagocytes to support its pathogenic lifestyle. S. aureus strains can produce up to five beta-barrel, bi-component, pore-forming leukocidins that target and kill host phagocytes. Thus, preventing immune cell killing by these toxins is likely to boost host immunity. Here, we describe the identification of glycine-rich motifs within the membrane-penetrating stem domains of the leukocidin subunits that are critical for killing primary human neutrophils. Remarkably, leukocidins lacking these glycine-rich motifs exhibit dominant-negative inhibitory effects toward their wild-type toxin counterparts as well as other leukocidins. Biochemical and cellular assays revealed that these dominant-negative toxins work by forming mixed complexes that are impaired in pore formation. The dominant-negative leukocidins inhibited S. aureus cytotoxicity toward primary human neutrophils, protected mice from lethal challenge by wild-type leukocidin, and reduced bacterial burden in a murine model of bloodstream infection. Thus, we describe the first example of staphylococcal bi-component dominant-negative toxins and their potential as novel therapeutics to combat S. aureus infection.

| S-EPMC4772982 | biostudies-literature

Mode of action of the antimicrobial peptide Mel4 is independent of Staphylococcus aureus cell membrane permeability.

Project description:Mel4 is a novel cationic peptide with potent activity against Gram-positive bacteria. The current study examined the anti-staphylococcal mechanism of action of Mel4 and its precursor peptide melimine. The interaction of peptides with lipoteichoic acid (LTA) and with the cytoplasmic membrane using DiSC(3)-5, Sytox green, Syto-9 and PI dyes were studied. Release of ATP and DNA/RNA from cells exposed to the peptides were determined. Bacteriolysis and autolysin-activated cell death were determined by measuring decreases in OD620nm and killing of Micrococcus lysodeikticus cells by cell-free media. Both peptides bound to LTA and rapidly dissipated the membrane potential (within 30 seconds) without affecting bacterial viability. Disturbance of the membrane potential was followed by the release of ATP (50% of total cellular ATP) by melimine and by Mel4 (20%) after 2 minutes exposure (p<0.001). Mel4 resulted in staphylococcal cells taking up PI with 3.9% cells predominantly stained after 150 min exposure, whereas melimine showed 34% staining. Unlike melimine, Mel4 did not release DNA/RNA. Cell-free media from Mel4 treated cells hydrolysed peptidoglycan and produced greater zones of inhibition against M. lysodeikticus lawn than melimine treated samples. These findings suggest that pore formation is unlikely to be involved in Mel4-mediated membrane destabilization for staphylococci, since there was no significant Mel4-induced PI staining and DNA/RNA leakage. It is likely that the S. aureus killing mechanism of Mel4 involves the release of autolysins followed by cell death. Whereas, membrane interaction is the primary bactericidal activity of melimine, which includes membrane depolarization, pore formation, release of cellular contents leading to cell death.

| S-EPMC6663011 | biostudies-literature

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Project description:Staphylococcus aureus is a Gram-positive bacterium that has become the leading cause of hospital acquired infections in the US. Repurposing Food and Drug Administration (FDA) approved drugs for antimicrobial therapy involves lower risks and costs compared to de novo development of novel antimicrobial agents. In this study, we examined the antimicrobial properties of two commercially available anthelmintic drugs. The FDA approved drug niclosamide and the veterinary drug oxyclozanide displayed strong in vivo and in vitro activity against methicillin resistant S. aureus (minimum inhibitory concentration (MIC): 0.125 and 0.5 ?g/ml respectively; minimum effective concentration: ? 0.78 ?g/ml for both drugs). The two drugs were also effective against another Gram-positive bacteria Enterococcus faecium (MIC 0.25 and 2 ?g/ml respectively), but not against the Gram-negative species Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter aerogenes. The in vitro antimicrobial activity of niclosamide and oxyclozanide were determined against methicillin, vancomycin, linezolid or daptomycin resistant S. aureus clinical isolates, with MICs at 0.0625-0.5 and 0.125-2 ?g/ml for niclosamide and oxyclozanide respectively. A time-kill study demonstrated that niclosamide is bacteriostatic, whereas oxyclozanide is bactericidal. Interestingly, oxyclozanide permeabilized the bacterial membrane but neither of the anthelmintic drugs exhibited demonstrable toxicity to sheep erythrocytes. Oxyclozanide was non-toxic to HepG2 human liver carcinoma cells within the range of its in vitro MICs but niclosamide displayed toxicity even at low concentrations. These data show that the salicylanilide anthelmintic drugs niclosamide and oxyclozanide are suitable candidates for mechanism of action studies and further clinical evaluation for treatment of staphylococcal infections.

| S-EPMC4405337 | biostudies-literature

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