Subinhibitory Clindamycin Differentially Inhibits Transcription of Exoprotein Genes in
            <i>Staphylococcus aureus</i>

Herbert, Silvia; Barry, Peter A.; Novick, Richard P.

doi:10.1128/iai.69.5.2996-3003.2001

Cited by 126 publications

(122 citation statements)

References 35 publications

(24 reference statements)

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“…However, several questions remain to be answered. (i) Why or how did lincomycin at subinhibitory concentrations alter the production of cytoplasmic proteins in S. coelicolor A3(2), despite the fact that in S. aureus there was no effect of subinhibitory lincosamide antibiotics on cytoplasmic protein production, as previously reported (36,37)? (ii) Why did cells treated with lincomy- cin show high levels of ATP despite the reduced levels of ATP synthase?…”

Section: Discussionmentioning

confidence: 85%

Lincomycin at Subinhibitory Concentrations Potentiates Secondary Metabolite Production by Streptomyces spp

Imai

Sato

Tanaka

et al. 2015

Appl Environ Microbiol

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e Antibiotics have either bactericidal or bacteriostatic activity. However, they also induce considerable gene expression in bacteria when used at subinhibitory concentrations (below the MIC). We found that lincomycin, which inhibits protein synthesis by binding to the ribosomes of Gram-positive bacteria, was effective for inducing the expression of genes involved in secondary metabolism in Streptomyces strains when added to medium at subinhibitory concentrations. In Streptomyces coelicolor A3(2), lincomycin at 1/10 of its MIC markedly increased the expression of the pathway-specific regulatory gene actII-ORF4 in the bluepigmented antibiotic actinorhodin (ACT) biosynthetic gene cluster, which resulted in ACT overproduction. Intriguingly, S. lividans 1326 grown in the presence of lincomycin at a subinhibitory concentration (1/12 or 1/3 of its MIC) produced abundant antibacterial compounds that were not detected in cells grown in lincomycin-free medium. Bioassay and mass spectrometry analysis revealed that some antibacterial compounds were novel congeners of calcium-dependent antibiotics. Our results indicate that lincomycin at subinhibitory concentrations potentiates the production of secondary metabolites in Streptomyces strains and suggest that activating these strains by utilizing the dose-response effects of lincomycin could be used to effectively induce the production of cryptic secondary metabolites. In addition to these findings, we also report that lincomycin used at concentrations for markedly increased ACT production resulted in alteration of the cytoplasmic protein (F o F 1 ATP synthase ␣ and ␤ subunits, etc.) profile and increased intracellular ATP levels. A fundamental mechanism for these unique phenomena is also discussed. Streptomyces is the largest genus of Gram-positive filamentous actinomycetes, and members of this genus produce abundant amounts of numerous bioactive metabolites, including antitumor agents, immunosuppressants, and antibiotics in particular (1, 2). Whole-genome sequencing studies of Streptomyces strains have shown that each species could produce many more secondary metabolites than were expected. For example, Streptomyces coelicolor A3(2), S. avermitilis MA-4680, and S. griseus IFO 13350 each produce several secondary metabolites, although they have more than 20 gene clusters that can encode a number of known or predicted biosynthetic pathways for secondary metabolites (3-5). This indicates that the vast majority of secondary metabolites remain unexpressed or barely expressed under standard laboratory conditions. Thus, there is considerable interest in exploring practical means to induce this genetic potential in streptomycetes, which could result in the isolation of novel bioactive secondary metabolites.Recent developments in new methodologies, including physiological and genetic engineering approaches, have opened the door for the discovery of novel secondary metabolites by activating cryptic biosynthetic pathways in streptomycetes (6-13). The improvements and modifications of ...

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Section: Discussionmentioning

confidence: 85%

Lincomycin at Subinhibitory Concentrations Potentiates Secondary Metabolite Production by Streptomyces spp

Imai

Sato

Tanaka

et al. 2015

Appl Environ Microbiol

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“…Strains bearing the plasmids pDT33 and pDT34 were cultured in the presence of erythromycin to select for the presence of the plasmid. Given the potential effect of antibiotics on exoprotein gene transcription (13), the data obtained with pDT34 should be compared only to values for the control bearing pDT33, and these values should not be compared with values obtained from plasmid-free strains.…”

Section: Tagacaaatataaaaagtgtata-----------------------------------mentioning

confidence: 99%

Accessory Gene Regulator Control of Staphyloccoccal Enterotoxin D Gene Expression

Tseng

Zhang²,

Stewart

2004

J Bacteriol

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The quorum-sensing system of Staphylococcus aureus, the accessory gene regulator (Agr) system, is responsible for increased transcription of certain exoprotein genes and decreased transcription of certain cell wall-associated proteins during the postexponential phase of growth. This regulation is important for virulence, as evidenced by a reduction in virulence associated with a loss of the Agr system. The enterotoxin D (sed) determinant is upregulated by the Agr system. To define the Agr-regulated cis element(s) within the sed promoter region, we utilized promoters not regulated by Agr to create hybrid promoters. Hybrid promoters were created by using sed sequences combined with the enterotoxin A (sea) promoter or the S. aureus lac operon promoter sequences. The results obtained indicated that the Agr control element of the sed promoter resides within the ؊35 promoter element and at the Pribnow box to the ؉1 site of the promoter. At these positions of the sed promoter, a directly repeated 6-bp sequence was found. This repeat is important for overall promoter activity, and maximal regulation of the promoter activity requires both repeat elements. Furthermore, Agr control of sed promoter activity was found to be dependent upon the presence of a functional Rot protein. Therefore, the postexponential increase in sed transcription results from the Agr-mediated reduction in Rot activity rather than as a direct effect of the Agr system.Staphylococcus aureus is a significant human pathogen which causes a wide range of diseases, including cutaneous infections, food poisoning, endocarditis, pneumonia, osteomyelitis, and septic arthritis (7,23,40). The virulence factors of this organism include a variety of exoproteins and cell wall-associated proteins (1). The exotoxins include enterotoxins (A to E and G to R); leukotoxin; exofoliative toxins; alpha-, beta-, gamma-, and delta-hemolytic toxins; toxic shock syndrome toxin; coagulase; and secreted enzymes, such as nuclease and proteases

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“…This effect has been shown when pathogens are exposed to subinhibitory concentrations of antibiotics. For instance, subinhibitory concentrations of clindamycin and linezolid have the ability to downregulate the expression of Staphylococcus aureus exotoxins, including a-haemolysin (hla) (Herbert et al, 2001;Bernardo et al, 2004). In contrast, subinhibitory concentrations of the cell-wall-acting b-lactam antibiotics have been shown to induce the expression of hla (Ohlsen et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Amphibian antimicrobial peptide fallaxin analogue FL9 affects virulence gene expression and DNA replication in Staphylococcus aureus

Gottschalk

Gottlieb

Vestergaard

et al. 2015

Journal of Medical Microbiology

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The rapid rise in antibiotic-resistant pathogens is causing increased health concerns, and consequently there is an urgent need for novel antimicrobial agents. Antimicrobial peptides (AMPs), which have been isolated from a wide range of organisms, represent a very promising class of novel antimicrobials. In the present study, the analogue FL9, based on the amphibian AMP fallaxin, was studied to elucidate its mode of action and antibacterial activity against the human pathogen Staphylococcus aureus. Our data showed that FL9 may have a dual mode of action against S. aureus. At concentrations around the MIC, FL9 bound DNA, inhibited DNA synthesis and induced the SOS DNA damage response, whereas at concentrations above the MIC the interaction between S. aureus and FL9 led to membrane disruption. The antibacterial activity of the peptide was maintained over a wide range of NaCl and MgCl 2 concentrations and at alkaline pH, while it was compromised by acidic pH and exposure to serum. Furthermore, at subinhibitory concentrations of FL9, S. aureus responded by increasing the expression of two major virulence factor genes, namely the regulatory rnaIII and hla, encoding a-haemolysin. In addition, the S. aureus-encoded natural tolerance mechanisms included peptide cleavage and the addition of positive charge to the cell surface, both of which minimized the antimicrobial activity of FL9. Our results add new information about FL9 and its effect on S. aureus, which may aid in the future development of analogues with improved therapeutic potential.

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Subinhibitory Clindamycin Differentially Inhibits Transcription of Exoprotein Genes in Staphylococcus aureus

Cited by 126 publications

References 35 publications

Lincomycin at Subinhibitory Concentrations Potentiates Secondary Metabolite Production by Streptomyces spp

Lincomycin at Subinhibitory Concentrations Potentiates Secondary Metabolite Production by Streptomyces spp

Accessory Gene Regulator Control of Staphyloccoccal Enterotoxin D Gene Expression

Amphibian antimicrobial peptide fallaxin analogue FL9 affects virulence gene expression and DNA replication in Staphylococcus aureus

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