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Valproic Acid Induces Antimicrobial Compound Production in Doratomyces microspores.

Zutz C, Bacher M, Parich A, Kluger B, Gacek-Matthews A, Schuhmacher R, Wagner M, Rychli K, Strauss J - Front Microbiol (2016)

Bottom Line: One approach is the use of small molecule effectors, potentially influencing chromatin landscape in fungi.Furthermore three compounds, cPM, cFP, and PAA, were able to boost the antimicrobial activity of other antimicrobial compounds. cPM, for the first time isolated from fungi, and to a lesser extent PAA, are even able to decrease the minimal inhibitory concentration of ampicillin in MRSA strains.In conclusion we could show in this study that VPA treatment is a potent tool for induction of "cryptic" antimicrobial compound production in fungi, and that the induced compounds are not exclusively linked to the secondary metabolism.

View Article: PubMed Central - PubMed

Affiliation: Institute for Milk Hygiene, University of Veterinary Medicine ViennaVienna, Austria; Research Platform Bioactive Microbial Metabolites, Bioresources and Technologies Campus in TullnTulln an der Donau, Austria.

ABSTRACT
One of the biggest challenges in public health is the rising number of antibiotic resistant pathogens and the lack of novel antibiotics. In recent years there is a rising focus on fungi as sources of antimicrobial compounds due to their ability to produce a large variety of bioactive compounds and the observation that virtually every fungus may still contain yet unknown so called "cryptic," often silenced, compounds. These putative metabolites could include novel bioactive compounds. Considerable effort is spent on methods to induce production of these "cryptic" metabolites. One approach is the use of small molecule effectors, potentially influencing chromatin landscape in fungi. We observed that the supernatant of the fungus Doratomyces (D.) microsporus treated with valproic acid (VPA) displayed antimicrobial activity against Staphylococcus (S.) aureus and two methicillin resistant clinical S. aureus isolates. VPA treatment resulted in enhanced production of seven antimicrobial compounds: cyclo-(L-proline-L-methionine) (cPM), p-hydroxybenzaldehyde, cyclo-(phenylalanine-proline) (cFP), indole-3-carboxylic acid, phenylacetic acid (PAA) and indole-3-acetic acid. The production of the antimicrobial compound phenyllactic acid was exclusively detectable after VPA treatment. Furthermore three compounds, cPM, cFP, and PAA, were able to boost the antimicrobial activity of other antimicrobial compounds. cPM, for the first time isolated from fungi, and to a lesser extent PAA, are even able to decrease the minimal inhibitory concentration of ampicillin in MRSA strains. In conclusion we could show in this study that VPA treatment is a potent tool for induction of "cryptic" antimicrobial compound production in fungi, and that the induced compounds are not exclusively linked to the secondary metabolism. Furthermore this is the first discovery of the rare diketopiperazine cPM in fungi. Additionally we could demonstrate that cPM and PAA boost antibiotic activity against antibiotic resistant strains, suggesting a possible application in combinatorial antibiotic treatment against resistant pathogens.

No MeSH data available.


Related in: MedlinePlus

Effect of combined compounds on antimicrobial activity. Effect of PLA (0.5 g/l) and PAA (1 g/l) alone and combined (A), and effect of the diketopiperazine cPM (1 g/l) and PLA (0.5 g/l) alone and combined (B) on the growth of S. aureus. (C) Effect of ampicillin (10 mg/l) and cPM (100 mg/l) alone and combined on the growth of S. aureus MRSA strain B335466. Data are presented as mean values ± standard deviations of three biological replicates performed in triplicate.
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Figure 5: Effect of combined compounds on antimicrobial activity. Effect of PLA (0.5 g/l) and PAA (1 g/l) alone and combined (A), and effect of the diketopiperazine cPM (1 g/l) and PLA (0.5 g/l) alone and combined (B) on the growth of S. aureus. (C) Effect of ampicillin (10 mg/l) and cPM (100 mg/l) alone and combined on the growth of S. aureus MRSA strain B335466. Data are presented as mean values ± standard deviations of three biological replicates performed in triplicate.

Mentions: The effect of combinations of the identified compounds (concentrations from 0.002 to 2 g/l) on the antimicrobial activity was determined against S. aureus, P. aeruginosa and C. albicans (Supplementary Table S3). The combination of PAA and PLA decreased the MIC value to 1 g/l against S. aureus (Figure 5A). The antimicrobial activity of PLA was additionally increased in the presence of the diketopiperazine cPM (Figure 5B). All antimicrobial active compounds except cPM and cFP showed increased antimicrobial activity against S. aureus and P. aeruginosa if combined with PAA. Combination of cPM, PAA and PLA lead to synergistic increase of antimicrobial activity of PLA (Supplementary Table S3).


Valproic Acid Induces Antimicrobial Compound Production in Doratomyces microspores.

Zutz C, Bacher M, Parich A, Kluger B, Gacek-Matthews A, Schuhmacher R, Wagner M, Rychli K, Strauss J - Front Microbiol (2016)

Effect of combined compounds on antimicrobial activity. Effect of PLA (0.5 g/l) and PAA (1 g/l) alone and combined (A), and effect of the diketopiperazine cPM (1 g/l) and PLA (0.5 g/l) alone and combined (B) on the growth of S. aureus. (C) Effect of ampicillin (10 mg/l) and cPM (100 mg/l) alone and combined on the growth of S. aureus MRSA strain B335466. Data are presented as mean values ± standard deviations of three biological replicates performed in triplicate.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4829596&req=5

Figure 5: Effect of combined compounds on antimicrobial activity. Effect of PLA (0.5 g/l) and PAA (1 g/l) alone and combined (A), and effect of the diketopiperazine cPM (1 g/l) and PLA (0.5 g/l) alone and combined (B) on the growth of S. aureus. (C) Effect of ampicillin (10 mg/l) and cPM (100 mg/l) alone and combined on the growth of S. aureus MRSA strain B335466. Data are presented as mean values ± standard deviations of three biological replicates performed in triplicate.
Mentions: The effect of combinations of the identified compounds (concentrations from 0.002 to 2 g/l) on the antimicrobial activity was determined against S. aureus, P. aeruginosa and C. albicans (Supplementary Table S3). The combination of PAA and PLA decreased the MIC value to 1 g/l against S. aureus (Figure 5A). The antimicrobial activity of PLA was additionally increased in the presence of the diketopiperazine cPM (Figure 5B). All antimicrobial active compounds except cPM and cFP showed increased antimicrobial activity against S. aureus and P. aeruginosa if combined with PAA. Combination of cPM, PAA and PLA lead to synergistic increase of antimicrobial activity of PLA (Supplementary Table S3).

Bottom Line: One approach is the use of small molecule effectors, potentially influencing chromatin landscape in fungi.Furthermore three compounds, cPM, cFP, and PAA, were able to boost the antimicrobial activity of other antimicrobial compounds. cPM, for the first time isolated from fungi, and to a lesser extent PAA, are even able to decrease the minimal inhibitory concentration of ampicillin in MRSA strains.In conclusion we could show in this study that VPA treatment is a potent tool for induction of "cryptic" antimicrobial compound production in fungi, and that the induced compounds are not exclusively linked to the secondary metabolism.

View Article: PubMed Central - PubMed

Affiliation: Institute for Milk Hygiene, University of Veterinary Medicine ViennaVienna, Austria; Research Platform Bioactive Microbial Metabolites, Bioresources and Technologies Campus in TullnTulln an der Donau, Austria.

ABSTRACT
One of the biggest challenges in public health is the rising number of antibiotic resistant pathogens and the lack of novel antibiotics. In recent years there is a rising focus on fungi as sources of antimicrobial compounds due to their ability to produce a large variety of bioactive compounds and the observation that virtually every fungus may still contain yet unknown so called "cryptic," often silenced, compounds. These putative metabolites could include novel bioactive compounds. Considerable effort is spent on methods to induce production of these "cryptic" metabolites. One approach is the use of small molecule effectors, potentially influencing chromatin landscape in fungi. We observed that the supernatant of the fungus Doratomyces (D.) microsporus treated with valproic acid (VPA) displayed antimicrobial activity against Staphylococcus (S.) aureus and two methicillin resistant clinical S. aureus isolates. VPA treatment resulted in enhanced production of seven antimicrobial compounds: cyclo-(L-proline-L-methionine) (cPM), p-hydroxybenzaldehyde, cyclo-(phenylalanine-proline) (cFP), indole-3-carboxylic acid, phenylacetic acid (PAA) and indole-3-acetic acid. The production of the antimicrobial compound phenyllactic acid was exclusively detectable after VPA treatment. Furthermore three compounds, cPM, cFP, and PAA, were able to boost the antimicrobial activity of other antimicrobial compounds. cPM, for the first time isolated from fungi, and to a lesser extent PAA, are even able to decrease the minimal inhibitory concentration of ampicillin in MRSA strains. In conclusion we could show in this study that VPA treatment is a potent tool for induction of "cryptic" antimicrobial compound production in fungi, and that the induced compounds are not exclusively linked to the secondary metabolism. Furthermore this is the first discovery of the rare diketopiperazine cPM in fungi. Additionally we could demonstrate that cPM and PAA boost antibiotic activity against antibiotic resistant strains, suggesting a possible application in combinatorial antibiotic treatment against resistant pathogens.

No MeSH data available.


Related in: MedlinePlus