The Polycyclic Polyprenylated Acylphloroglucinol Antibiotic PPAP 23 Targets the Membrane and Iron Metabolism in Staphylococcus aureus
Recently, a series of endo-type B polycyclic polyprenylated acylphloroglucinols (PPAP) derivatives with high antimicrobial activities were chemically synthesized. One of the derivatives, PPAP 23, which showed high antimicrobial activity and low cytotoxicity, was chosen for further investigation of i...
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Frontiers Media S.A.
2019-01-01
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| Series: | Frontiers in Microbiology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fmicb.2019.00014/full |
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| author | Huanhuan Wang Frank Kraus Peter Popella Aslihan Baykal Claudia Guttroff Patrice François Peter Sass Bernd Plietker Friedrich Götz |
| author_facet | Huanhuan Wang Frank Kraus Peter Popella Aslihan Baykal Claudia Guttroff Patrice François Peter Sass Bernd Plietker Friedrich Götz |
| author_sort | Huanhuan Wang |
| collection | DOAJ |
| description | Recently, a series of endo-type B polycyclic polyprenylated acylphloroglucinols (PPAP) derivatives with high antimicrobial activities were chemically synthesized. One of the derivatives, PPAP 23, which showed high antimicrobial activity and low cytotoxicity, was chosen for further investigation of its bactericidal profiles and mode of action. PPAP 23 showed a better efficacy in killing methicillin resistant Staphylococcus aureus (MRSA) and decreasing the metabolic activity of 5-day-old biofilm cells than vancomycin. Moreover, S. aureus did not appear to develop resistance against PPAP 23. The antimicrobial mechanism of PPAP 23 was investigated by RNA-seq combined with phenotypic and biochemical approaches. RNA-seq suggested that PPAP 23 signaled iron overload to the bacterial cells because genes involved in iron transport were downregulated and iron storage gene was upregulated by PPAP 23. PPAP 23 affected the membrane integrity but did not induce pore formation; it inhibited bacterial respiration. PPAP 23 preferentially inhibited Fe–S cluster enzymes; it has a mild iron chelating activity and supplementation of exogenous iron attenuated its antimicrobial activity. PPAP 23 was more effective in inhibiting the growth of S. aureus under iron-restricted condition. The crystal structure of a benzylated analog of PPAP 23 showed a highly defined octahedral coordination of three PPAP ligands around a Fe (3+) core. This suggests that PPAPs are generally capable of iron chelation and are able to form defined stable complexes. PPAP 23 was found to induce reactive oxygen species (ROS) and oxidative stress. Fluorescence microscopic analysis showed that PPAP 23 caused an enlargement of the bacterial cells, perturbed the membrane, and dislocated the nucleoid. Taken together, we postulate that PPAP 23 interacts with the cytoplasmic membrane with its hydrophobic pocket and interferes with the iron metabolism to exert its antimicrobial activity in Staphylococcus aureus. |
| first_indexed | 2024-12-17T12:49:40Z |
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| issn | 1664-302X |
| language | English |
| last_indexed | 2024-12-17T12:49:40Z |
| publishDate | 2019-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Microbiology |
| spelling | doaj.art-f5cf5789fb634fa4930243a05ecba4882022-12-21T21:47:38ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2019-01-011010.3389/fmicb.2019.00014427072The Polycyclic Polyprenylated Acylphloroglucinol Antibiotic PPAP 23 Targets the Membrane and Iron Metabolism in Staphylococcus aureusHuanhuan Wang0Frank Kraus1Peter Popella2Aslihan Baykal3Claudia Guttroff4Patrice François5Peter Sass6Bernd Plietker7Friedrich Götz8Microbial Genetics, Interfaculty Institute of Microbiology and Infection Medicine (IMIT), University of Tübingen, Tübingen, GermanyInstitut für Organische Chemie, Universität Stuttgart, Stuttgart, GermanyMicrobial Genetics, Interfaculty Institute of Microbiology and Infection Medicine (IMIT), University of Tübingen, Tübingen, GermanyInstitut für Organische Chemie, Universität Stuttgart, Stuttgart, GermanyInstitut für Organische Chemie, Universität Stuttgart, Stuttgart, GermanyGenomic Research Laboratory, Division of Infectious Diseases, Geneva University Hospital, Geneva, SwitzerlandMicrobial Bioactive Compounds, Interfaculty Institute of Microbiology and Infection Medicine (IMIT), University of Tübingen, Tübingen, GermanyInstitut für Organische Chemie, Universität Stuttgart, Stuttgart, GermanyMicrobial Genetics, Interfaculty Institute of Microbiology and Infection Medicine (IMIT), University of Tübingen, Tübingen, GermanyRecently, a series of endo-type B polycyclic polyprenylated acylphloroglucinols (PPAP) derivatives with high antimicrobial activities were chemically synthesized. One of the derivatives, PPAP 23, which showed high antimicrobial activity and low cytotoxicity, was chosen for further investigation of its bactericidal profiles and mode of action. PPAP 23 showed a better efficacy in killing methicillin resistant Staphylococcus aureus (MRSA) and decreasing the metabolic activity of 5-day-old biofilm cells than vancomycin. Moreover, S. aureus did not appear to develop resistance against PPAP 23. The antimicrobial mechanism of PPAP 23 was investigated by RNA-seq combined with phenotypic and biochemical approaches. RNA-seq suggested that PPAP 23 signaled iron overload to the bacterial cells because genes involved in iron transport were downregulated and iron storage gene was upregulated by PPAP 23. PPAP 23 affected the membrane integrity but did not induce pore formation; it inhibited bacterial respiration. PPAP 23 preferentially inhibited Fe–S cluster enzymes; it has a mild iron chelating activity and supplementation of exogenous iron attenuated its antimicrobial activity. PPAP 23 was more effective in inhibiting the growth of S. aureus under iron-restricted condition. The crystal structure of a benzylated analog of PPAP 23 showed a highly defined octahedral coordination of three PPAP ligands around a Fe (3+) core. This suggests that PPAPs are generally capable of iron chelation and are able to form defined stable complexes. PPAP 23 was found to induce reactive oxygen species (ROS) and oxidative stress. Fluorescence microscopic analysis showed that PPAP 23 caused an enlargement of the bacterial cells, perturbed the membrane, and dislocated the nucleoid. Taken together, we postulate that PPAP 23 interacts with the cytoplasmic membrane with its hydrophobic pocket and interferes with the iron metabolism to exert its antimicrobial activity in Staphylococcus aureus.https://www.frontiersin.org/article/10.3389/fmicb.2019.00014/fullantibioticPPAP 23mode of actioniron metabolismStaphylococciMRSA |
| spellingShingle | Huanhuan Wang Frank Kraus Peter Popella Aslihan Baykal Claudia Guttroff Patrice François Peter Sass Bernd Plietker Friedrich Götz The Polycyclic Polyprenylated Acylphloroglucinol Antibiotic PPAP 23 Targets the Membrane and Iron Metabolism in Staphylococcus aureus Frontiers in Microbiology antibiotic PPAP 23 mode of action iron metabolism Staphylococci MRSA |
| title | The Polycyclic Polyprenylated Acylphloroglucinol Antibiotic PPAP 23 Targets the Membrane and Iron Metabolism in Staphylococcus aureus |
| title_full | The Polycyclic Polyprenylated Acylphloroglucinol Antibiotic PPAP 23 Targets the Membrane and Iron Metabolism in Staphylococcus aureus |
| title_fullStr | The Polycyclic Polyprenylated Acylphloroglucinol Antibiotic PPAP 23 Targets the Membrane and Iron Metabolism in Staphylococcus aureus |
| title_full_unstemmed | The Polycyclic Polyprenylated Acylphloroglucinol Antibiotic PPAP 23 Targets the Membrane and Iron Metabolism in Staphylococcus aureus |
| title_short | The Polycyclic Polyprenylated Acylphloroglucinol Antibiotic PPAP 23 Targets the Membrane and Iron Metabolism in Staphylococcus aureus |
| title_sort | polycyclic polyprenylated acylphloroglucinol antibiotic ppap 23 targets the membrane and iron metabolism in staphylococcus aureus |
| topic | antibiotic PPAP 23 mode of action iron metabolism Staphylococci MRSA |
| url | https://www.frontiersin.org/article/10.3389/fmicb.2019.00014/full |
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