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Meleagrin, a new FabI inhibitor from Penicillium chryosogenum with at least one additional mode of action.

Zheng CJ, Sohn MJ, Lee S, Kim WG - PLoS ONE (2013)

Bottom Line: Bacterial enoyl-acyl carrier protein reductase (FabI) is a promising novel antibacterial target.The compounds that were not effective against the FabK isoform, however, inhibited the growth of Streptococcus pneumoniae that contained only the FabK isoform.These results demonstrate that the compounds inhibited another target in addition to FabI.

View Article: PubMed Central - PubMed

Affiliation: Superbacteria Research Center, Korea Research Institute of Bioscience and Biotechnology, Yusong, Daejeon, Republic of Korea.

ABSTRACT
Bacterial enoyl-acyl carrier protein reductase (FabI) is a promising novel antibacterial target. We isolated a new class of FabI inhibitor from Penicillium chrysogenum, which produces various antibiotics, the mechanisms of some of them are unknown. The isolated FabI inhibitor was determined to be meleagrin by mass spectroscopy and nuclear magnetic resonance spectral analyses, and its more active and inactive derivatives were chemically prepared. Consistent with their selective inhibition of Staphylococcus aureus FabI, meleagrin and its more active derivatives directly bound to S. aureus FabI in a fluorescence quenching assay, inhibited intracellular fatty acid biosynthesis and growth of S. aureus, and increased the minimum inhibitory concentration for fabI-overexpressing S. aureus. The compounds that were not effective against the FabK isoform, however, inhibited the growth of Streptococcus pneumoniae that contained only the FabK isoform. Additionally no resistant mutant to the compounds was obtained. Importantly, fabK-overexpressing Escherichia coli was not resistant to these compounds, but was resistant to triclosan. These results demonstrate that the compounds inhibited another target in addition to FabI. Thus, meleagrin is a new class of FabI inhibitor with at least one additional mode of action that could have potential for treating multidrug-resistant bacteria.

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Meleagrin (1) and its chemically prepared derivatives.
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pone-0078922-g001: Meleagrin (1) and its chemically prepared derivatives.

Mentions: During our continued screening for FabI inhibitors from microbial metabolites, we found meleagrin (1) with a druggable structure during solid-state fermentation of a seashore slime-derived Penicillium chrysogenum, a penicillin-producing species (Figure 1). Here, we report the isolation and analog preparation of meleagrin, in addition to its inhibition of FabI isoforms and whole cells of various pathogenic bacteria, target validation, and its multitarget effect.


Meleagrin, a new FabI inhibitor from Penicillium chryosogenum with at least one additional mode of action.

Zheng CJ, Sohn MJ, Lee S, Kim WG - PLoS ONE (2013)

Meleagrin (1) and its chemically prepared derivatives.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3842914&req=5

pone-0078922-g001: Meleagrin (1) and its chemically prepared derivatives.
Mentions: During our continued screening for FabI inhibitors from microbial metabolites, we found meleagrin (1) with a druggable structure during solid-state fermentation of a seashore slime-derived Penicillium chrysogenum, a penicillin-producing species (Figure 1). Here, we report the isolation and analog preparation of meleagrin, in addition to its inhibition of FabI isoforms and whole cells of various pathogenic bacteria, target validation, and its multitarget effect.

Bottom Line: Bacterial enoyl-acyl carrier protein reductase (FabI) is a promising novel antibacterial target.The compounds that were not effective against the FabK isoform, however, inhibited the growth of Streptococcus pneumoniae that contained only the FabK isoform.These results demonstrate that the compounds inhibited another target in addition to FabI.

View Article: PubMed Central - PubMed

Affiliation: Superbacteria Research Center, Korea Research Institute of Bioscience and Biotechnology, Yusong, Daejeon, Republic of Korea.

ABSTRACT
Bacterial enoyl-acyl carrier protein reductase (FabI) is a promising novel antibacterial target. We isolated a new class of FabI inhibitor from Penicillium chrysogenum, which produces various antibiotics, the mechanisms of some of them are unknown. The isolated FabI inhibitor was determined to be meleagrin by mass spectroscopy and nuclear magnetic resonance spectral analyses, and its more active and inactive derivatives were chemically prepared. Consistent with their selective inhibition of Staphylococcus aureus FabI, meleagrin and its more active derivatives directly bound to S. aureus FabI in a fluorescence quenching assay, inhibited intracellular fatty acid biosynthesis and growth of S. aureus, and increased the minimum inhibitory concentration for fabI-overexpressing S. aureus. The compounds that were not effective against the FabK isoform, however, inhibited the growth of Streptococcus pneumoniae that contained only the FabK isoform. Additionally no resistant mutant to the compounds was obtained. Importantly, fabK-overexpressing Escherichia coli was not resistant to these compounds, but was resistant to triclosan. These results demonstrate that the compounds inhibited another target in addition to FabI. Thus, meleagrin is a new class of FabI inhibitor with at least one additional mode of action that could have potential for treating multidrug-resistant bacteria.

Show MeSH
Related in: MedlinePlus