Efficient Inhibition of Bacterial Biofilm Through Interference of Protein–Protein Interaction of Master Regulator Proteins: a Proof of Concept Study with SinR- SinI Complex of Bacillus subtilis
Abstract Biofilm-associated microbial growth is a major cause of environmental, industrial, and public health concern. Therefore, there is a pressing need to discover and develop efficient antibiofilm strategies. Regulatory proteins vital for biofilm formation might be ideal targets for developing n...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Kantiwal, Usha [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2022 |
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| Schlagwörter: |
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| Anmerkung: |
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. |
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| Übergeordnetes Werk: |
Enthalten in: Applied biochemistry and biotechnology - Berlin : Springer, 1976, 195(2022), 3 vom: 19. Nov., Seite 1947-1967 |
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| Übergeordnetes Werk: |
volume:195 ; year:2022 ; number:3 ; day:19 ; month:11 ; pages:1947-1967 |
| Links: |
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| DOI / URN: |
10.1007/s12010-022-04231-w |
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SPR049335030 |
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| 520 | |a Abstract Biofilm-associated microbial growth is a major cause of environmental, industrial, and public health concern. Therefore, there is a pressing need to discover and develop efficient antibiofilm strategies. Regulatory proteins vital for biofilm formation might be ideal targets for developing novel antibiofilm therapeutics. Their activities often depend on protein–protein interactions. Therefore, such targets present unique opportunities and challenges to drug discovery. In Bacillus subtilis, a model organism for studying biofilms, SinR acts as the master regulator of the biofilm formation cascade. Under favourable growth conditions, it represses the epsA-O and tapA-sipW-tasA operons, which encode for essential structural components of biofilms. Under unfavourable growth conditions, SinI, an agonist protein, inactivates SinR by forming a heterotrimeric complex. This results in derepression of epsA-O and tapA-sipW-tasA operons and leads to the phenotypic switch from planktonic to biofilm-associated form. We hypothesized that inhibiting SinR–SinI interaction might warrant repression of epsA-O and tapA-sipW-tasA operons and inhibit biofilm formation. To evaluate this hypothesis, we carried out a drug repurposing study for identifying potential inhibitors of SinI. Cefoperazone and itraconazole were identified as potential inhibitors with virtual screening. The stability of their interaction with SinI was assessed in extended MD performed over 100 ns. Both cefoperazone and itraconazole showed stable interaction. In in vitro studies, cefoperazone hindered the interaction of purified recombinant SinI and SinR. In the whole cell-based biofilm inhibition assays also cefoperazone was found to efficiently inhibited biofilm formation. These results provide proof of concept for targeting protein–protein interaction of master regulators as potential target for discovery and development of antibiofilm therapeutics. We propose that similar drug repurposing studies targeting key regulators of biofilm formation cascade could be an efficient approach for discovering novel anti-biofilm therapeutics against priority pathogens. | ||
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10.1007/s12010-022-04231-w doi (DE-627)SPR049335030 (SPR)s12010-022-04231-w-e DE-627 ger DE-627 rakwb eng Kantiwal, Usha verfasserin aut Efficient Inhibition of Bacterial Biofilm Through Interference of Protein–Protein Interaction of Master Regulator Proteins: a Proof of Concept Study with SinR- SinI Complex of Bacillus subtilis 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. Abstract Biofilm-associated microbial growth is a major cause of environmental, industrial, and public health concern. Therefore, there is a pressing need to discover and develop efficient antibiofilm strategies. Regulatory proteins vital for biofilm formation might be ideal targets for developing novel antibiofilm therapeutics. Their activities often depend on protein–protein interactions. Therefore, such targets present unique opportunities and challenges to drug discovery. In Bacillus subtilis, a model organism for studying biofilms, SinR acts as the master regulator of the biofilm formation cascade. Under favourable growth conditions, it represses the epsA-O and tapA-sipW-tasA operons, which encode for essential structural components of biofilms. Under unfavourable growth conditions, SinI, an agonist protein, inactivates SinR by forming a heterotrimeric complex. This results in derepression of epsA-O and tapA-sipW-tasA operons and leads to the phenotypic switch from planktonic to biofilm-associated form. We hypothesized that inhibiting SinR–SinI interaction might warrant repression of epsA-O and tapA-sipW-tasA operons and inhibit biofilm formation. To evaluate this hypothesis, we carried out a drug repurposing study for identifying potential inhibitors of SinI. Cefoperazone and itraconazole were identified as potential inhibitors with virtual screening. The stability of their interaction with SinI was assessed in extended MD performed over 100 ns. Both cefoperazone and itraconazole showed stable interaction. In in vitro studies, cefoperazone hindered the interaction of purified recombinant SinI and SinR. In the whole cell-based biofilm inhibition assays also cefoperazone was found to efficiently inhibited biofilm formation. These results provide proof of concept for targeting protein–protein interaction of master regulators as potential target for discovery and development of antibiofilm therapeutics. We propose that similar drug repurposing studies targeting key regulators of biofilm formation cascade could be an efficient approach for discovering novel anti-biofilm therapeutics against priority pathogens. Biofilms (dpeaa)DE-He213 Anti-biofilm therapeutics (dpeaa)DE-He213 Master regulator of biofilm formation (dpeaa)DE-He213 SinR–SinI complex (dpeaa)DE-He213 Cefoperazone (dpeaa)DE-He213 Pandey, Janmejay (orcid)0000-0003-0367-4089 aut Enthalten in Applied biochemistry and biotechnology Berlin : Springer, 1976 195(2022), 3 vom: 19. Nov., Seite 1947-1967 (DE-627)342894846 (DE-600)2072711-2 1559-0291 nnns volume:195 year:2022 number:3 day:19 month:11 pages:1947-1967 https://dx.doi.org/10.1007/s12010-022-04231-w lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 195 2022 3 19 11 1947-1967 |
| spelling |
10.1007/s12010-022-04231-w doi (DE-627)SPR049335030 (SPR)s12010-022-04231-w-e DE-627 ger DE-627 rakwb eng Kantiwal, Usha verfasserin aut Efficient Inhibition of Bacterial Biofilm Through Interference of Protein–Protein Interaction of Master Regulator Proteins: a Proof of Concept Study with SinR- SinI Complex of Bacillus subtilis 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. Abstract Biofilm-associated microbial growth is a major cause of environmental, industrial, and public health concern. Therefore, there is a pressing need to discover and develop efficient antibiofilm strategies. Regulatory proteins vital for biofilm formation might be ideal targets for developing novel antibiofilm therapeutics. Their activities often depend on protein–protein interactions. Therefore, such targets present unique opportunities and challenges to drug discovery. In Bacillus subtilis, a model organism for studying biofilms, SinR acts as the master regulator of the biofilm formation cascade. Under favourable growth conditions, it represses the epsA-O and tapA-sipW-tasA operons, which encode for essential structural components of biofilms. Under unfavourable growth conditions, SinI, an agonist protein, inactivates SinR by forming a heterotrimeric complex. This results in derepression of epsA-O and tapA-sipW-tasA operons and leads to the phenotypic switch from planktonic to biofilm-associated form. We hypothesized that inhibiting SinR–SinI interaction might warrant repression of epsA-O and tapA-sipW-tasA operons and inhibit biofilm formation. To evaluate this hypothesis, we carried out a drug repurposing study for identifying potential inhibitors of SinI. Cefoperazone and itraconazole were identified as potential inhibitors with virtual screening. The stability of their interaction with SinI was assessed in extended MD performed over 100 ns. Both cefoperazone and itraconazole showed stable interaction. In in vitro studies, cefoperazone hindered the interaction of purified recombinant SinI and SinR. In the whole cell-based biofilm inhibition assays also cefoperazone was found to efficiently inhibited biofilm formation. These results provide proof of concept for targeting protein–protein interaction of master regulators as potential target for discovery and development of antibiofilm therapeutics. We propose that similar drug repurposing studies targeting key regulators of biofilm formation cascade could be an efficient approach for discovering novel anti-biofilm therapeutics against priority pathogens. Biofilms (dpeaa)DE-He213 Anti-biofilm therapeutics (dpeaa)DE-He213 Master regulator of biofilm formation (dpeaa)DE-He213 SinR–SinI complex (dpeaa)DE-He213 Cefoperazone (dpeaa)DE-He213 Pandey, Janmejay (orcid)0000-0003-0367-4089 aut Enthalten in Applied biochemistry and biotechnology Berlin : Springer, 1976 195(2022), 3 vom: 19. Nov., Seite 1947-1967 (DE-627)342894846 (DE-600)2072711-2 1559-0291 nnns volume:195 year:2022 number:3 day:19 month:11 pages:1947-1967 https://dx.doi.org/10.1007/s12010-022-04231-w lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 195 2022 3 19 11 1947-1967 |
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10.1007/s12010-022-04231-w doi (DE-627)SPR049335030 (SPR)s12010-022-04231-w-e DE-627 ger DE-627 rakwb eng Kantiwal, Usha verfasserin aut Efficient Inhibition of Bacterial Biofilm Through Interference of Protein–Protein Interaction of Master Regulator Proteins: a Proof of Concept Study with SinR- SinI Complex of Bacillus subtilis 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. Abstract Biofilm-associated microbial growth is a major cause of environmental, industrial, and public health concern. Therefore, there is a pressing need to discover and develop efficient antibiofilm strategies. Regulatory proteins vital for biofilm formation might be ideal targets for developing novel antibiofilm therapeutics. Their activities often depend on protein–protein interactions. Therefore, such targets present unique opportunities and challenges to drug discovery. In Bacillus subtilis, a model organism for studying biofilms, SinR acts as the master regulator of the biofilm formation cascade. Under favourable growth conditions, it represses the epsA-O and tapA-sipW-tasA operons, which encode for essential structural components of biofilms. Under unfavourable growth conditions, SinI, an agonist protein, inactivates SinR by forming a heterotrimeric complex. This results in derepression of epsA-O and tapA-sipW-tasA operons and leads to the phenotypic switch from planktonic to biofilm-associated form. We hypothesized that inhibiting SinR–SinI interaction might warrant repression of epsA-O and tapA-sipW-tasA operons and inhibit biofilm formation. To evaluate this hypothesis, we carried out a drug repurposing study for identifying potential inhibitors of SinI. Cefoperazone and itraconazole were identified as potential inhibitors with virtual screening. The stability of their interaction with SinI was assessed in extended MD performed over 100 ns. Both cefoperazone and itraconazole showed stable interaction. In in vitro studies, cefoperazone hindered the interaction of purified recombinant SinI and SinR. In the whole cell-based biofilm inhibition assays also cefoperazone was found to efficiently inhibited biofilm formation. These results provide proof of concept for targeting protein–protein interaction of master regulators as potential target for discovery and development of antibiofilm therapeutics. We propose that similar drug repurposing studies targeting key regulators of biofilm formation cascade could be an efficient approach for discovering novel anti-biofilm therapeutics against priority pathogens. Biofilms (dpeaa)DE-He213 Anti-biofilm therapeutics (dpeaa)DE-He213 Master regulator of biofilm formation (dpeaa)DE-He213 SinR–SinI complex (dpeaa)DE-He213 Cefoperazone (dpeaa)DE-He213 Pandey, Janmejay (orcid)0000-0003-0367-4089 aut Enthalten in Applied biochemistry and biotechnology Berlin : Springer, 1976 195(2022), 3 vom: 19. Nov., Seite 1947-1967 (DE-627)342894846 (DE-600)2072711-2 1559-0291 nnns volume:195 year:2022 number:3 day:19 month:11 pages:1947-1967 https://dx.doi.org/10.1007/s12010-022-04231-w lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 195 2022 3 19 11 1947-1967 |
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10.1007/s12010-022-04231-w doi (DE-627)SPR049335030 (SPR)s12010-022-04231-w-e DE-627 ger DE-627 rakwb eng Kantiwal, Usha verfasserin aut Efficient Inhibition of Bacterial Biofilm Through Interference of Protein–Protein Interaction of Master Regulator Proteins: a Proof of Concept Study with SinR- SinI Complex of Bacillus subtilis 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. Abstract Biofilm-associated microbial growth is a major cause of environmental, industrial, and public health concern. Therefore, there is a pressing need to discover and develop efficient antibiofilm strategies. Regulatory proteins vital for biofilm formation might be ideal targets for developing novel antibiofilm therapeutics. Their activities often depend on protein–protein interactions. Therefore, such targets present unique opportunities and challenges to drug discovery. In Bacillus subtilis, a model organism for studying biofilms, SinR acts as the master regulator of the biofilm formation cascade. Under favourable growth conditions, it represses the epsA-O and tapA-sipW-tasA operons, which encode for essential structural components of biofilms. Under unfavourable growth conditions, SinI, an agonist protein, inactivates SinR by forming a heterotrimeric complex. This results in derepression of epsA-O and tapA-sipW-tasA operons and leads to the phenotypic switch from planktonic to biofilm-associated form. We hypothesized that inhibiting SinR–SinI interaction might warrant repression of epsA-O and tapA-sipW-tasA operons and inhibit biofilm formation. To evaluate this hypothesis, we carried out a drug repurposing study for identifying potential inhibitors of SinI. Cefoperazone and itraconazole were identified as potential inhibitors with virtual screening. The stability of their interaction with SinI was assessed in extended MD performed over 100 ns. Both cefoperazone and itraconazole showed stable interaction. In in vitro studies, cefoperazone hindered the interaction of purified recombinant SinI and SinR. In the whole cell-based biofilm inhibition assays also cefoperazone was found to efficiently inhibited biofilm formation. These results provide proof of concept for targeting protein–protein interaction of master regulators as potential target for discovery and development of antibiofilm therapeutics. We propose that similar drug repurposing studies targeting key regulators of biofilm formation cascade could be an efficient approach for discovering novel anti-biofilm therapeutics against priority pathogens. Biofilms (dpeaa)DE-He213 Anti-biofilm therapeutics (dpeaa)DE-He213 Master regulator of biofilm formation (dpeaa)DE-He213 SinR–SinI complex (dpeaa)DE-He213 Cefoperazone (dpeaa)DE-He213 Pandey, Janmejay (orcid)0000-0003-0367-4089 aut Enthalten in Applied biochemistry and biotechnology Berlin : Springer, 1976 195(2022), 3 vom: 19. Nov., Seite 1947-1967 (DE-627)342894846 (DE-600)2072711-2 1559-0291 nnns volume:195 year:2022 number:3 day:19 month:11 pages:1947-1967 https://dx.doi.org/10.1007/s12010-022-04231-w lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 195 2022 3 19 11 1947-1967 |
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10.1007/s12010-022-04231-w doi (DE-627)SPR049335030 (SPR)s12010-022-04231-w-e DE-627 ger DE-627 rakwb eng Kantiwal, Usha verfasserin aut Efficient Inhibition of Bacterial Biofilm Through Interference of Protein–Protein Interaction of Master Regulator Proteins: a Proof of Concept Study with SinR- SinI Complex of Bacillus subtilis 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. Abstract Biofilm-associated microbial growth is a major cause of environmental, industrial, and public health concern. Therefore, there is a pressing need to discover and develop efficient antibiofilm strategies. Regulatory proteins vital for biofilm formation might be ideal targets for developing novel antibiofilm therapeutics. Their activities often depend on protein–protein interactions. Therefore, such targets present unique opportunities and challenges to drug discovery. In Bacillus subtilis, a model organism for studying biofilms, SinR acts as the master regulator of the biofilm formation cascade. Under favourable growth conditions, it represses the epsA-O and tapA-sipW-tasA operons, which encode for essential structural components of biofilms. Under unfavourable growth conditions, SinI, an agonist protein, inactivates SinR by forming a heterotrimeric complex. This results in derepression of epsA-O and tapA-sipW-tasA operons and leads to the phenotypic switch from planktonic to biofilm-associated form. We hypothesized that inhibiting SinR–SinI interaction might warrant repression of epsA-O and tapA-sipW-tasA operons and inhibit biofilm formation. To evaluate this hypothesis, we carried out a drug repurposing study for identifying potential inhibitors of SinI. Cefoperazone and itraconazole were identified as potential inhibitors with virtual screening. The stability of their interaction with SinI was assessed in extended MD performed over 100 ns. Both cefoperazone and itraconazole showed stable interaction. In in vitro studies, cefoperazone hindered the interaction of purified recombinant SinI and SinR. In the whole cell-based biofilm inhibition assays also cefoperazone was found to efficiently inhibited biofilm formation. These results provide proof of concept for targeting protein–protein interaction of master regulators as potential target for discovery and development of antibiofilm therapeutics. We propose that similar drug repurposing studies targeting key regulators of biofilm formation cascade could be an efficient approach for discovering novel anti-biofilm therapeutics against priority pathogens. Biofilms (dpeaa)DE-He213 Anti-biofilm therapeutics (dpeaa)DE-He213 Master regulator of biofilm formation (dpeaa)DE-He213 SinR–SinI complex (dpeaa)DE-He213 Cefoperazone (dpeaa)DE-He213 Pandey, Janmejay (orcid)0000-0003-0367-4089 aut Enthalten in Applied biochemistry and biotechnology Berlin : Springer, 1976 195(2022), 3 vom: 19. Nov., Seite 1947-1967 (DE-627)342894846 (DE-600)2072711-2 1559-0291 nnns volume:195 year:2022 number:3 day:19 month:11 pages:1947-1967 https://dx.doi.org/10.1007/s12010-022-04231-w lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 195 2022 3 19 11 1947-1967 |
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Enthalten in Applied biochemistry and biotechnology 195(2022), 3 vom: 19. Nov., Seite 1947-1967 volume:195 year:2022 number:3 day:19 month:11 pages:1947-1967 |
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Enthalten in Applied biochemistry and biotechnology 195(2022), 3 vom: 19. Nov., Seite 1947-1967 volume:195 year:2022 number:3 day:19 month:11 pages:1947-1967 |
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Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Abstract Biofilm-associated microbial growth is a major cause of environmental, industrial, and public health concern. Therefore, there is a pressing need to discover and develop efficient antibiofilm strategies. Regulatory proteins vital for biofilm formation might be ideal targets for developing novel antibiofilm therapeutics. Their activities often depend on protein–protein interactions. Therefore, such targets present unique opportunities and challenges to drug discovery. In Bacillus subtilis, a model organism for studying biofilms, SinR acts as the master regulator of the biofilm formation cascade. Under favourable growth conditions, it represses the epsA-O and tapA-sipW-tasA operons, which encode for essential structural components of biofilms. Under unfavourable growth conditions, SinI, an agonist protein, inactivates SinR by forming a heterotrimeric complex. This results in derepression of epsA-O and tapA-sipW-tasA operons and leads to the phenotypic switch from planktonic to biofilm-associated form. We hypothesized that inhibiting SinR–SinI interaction might warrant repression of epsA-O and tapA-sipW-tasA operons and inhibit biofilm formation. To evaluate this hypothesis, we carried out a drug repurposing study for identifying potential inhibitors of SinI. Cefoperazone and itraconazole were identified as potential inhibitors with virtual screening. The stability of their interaction with SinI was assessed in extended MD performed over 100 ns. Both cefoperazone and itraconazole showed stable interaction. In in vitro studies, cefoperazone hindered the interaction of purified recombinant SinI and SinR. In the whole cell-based biofilm inhibition assays also cefoperazone was found to efficiently inhibited biofilm formation. These results provide proof of concept for targeting protein–protein interaction of master regulators as potential target for discovery and development of antibiofilm therapeutics. 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Kantiwal, Usha |
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Kantiwal, Usha misc Biofilms misc Anti-biofilm therapeutics misc Master regulator of biofilm formation misc SinR–SinI complex misc Cefoperazone Efficient Inhibition of Bacterial Biofilm Through Interference of Protein–Protein Interaction of Master Regulator Proteins: a Proof of Concept Study with SinR- SinI Complex of Bacillus subtilis |
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Efficient Inhibition of Bacterial Biofilm Through Interference of Protein–Protein Interaction of Master Regulator Proteins: a Proof of Concept Study with SinR- SinI Complex of Bacillus subtilis Biofilms (dpeaa)DE-He213 Anti-biofilm therapeutics (dpeaa)DE-He213 Master regulator of biofilm formation (dpeaa)DE-He213 SinR–SinI complex (dpeaa)DE-He213 Cefoperazone (dpeaa)DE-He213 |
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Efficient Inhibition of Bacterial Biofilm Through Interference of Protein–Protein Interaction of Master Regulator Proteins: a Proof of Concept Study with SinR- SinI Complex of Bacillus subtilis |
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Efficient Inhibition of Bacterial Biofilm Through Interference of Protein–Protein Interaction of Master Regulator Proteins: a Proof of Concept Study with SinR- SinI Complex of Bacillus subtilis |
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efficient inhibition of bacterial biofilm through interference of protein–protein interaction of master regulator proteins: a proof of concept study with sinr- sini complex of bacillus subtilis |
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Efficient Inhibition of Bacterial Biofilm Through Interference of Protein–Protein Interaction of Master Regulator Proteins: a Proof of Concept Study with SinR- SinI Complex of Bacillus subtilis |
| abstract |
Abstract Biofilm-associated microbial growth is a major cause of environmental, industrial, and public health concern. Therefore, there is a pressing need to discover and develop efficient antibiofilm strategies. Regulatory proteins vital for biofilm formation might be ideal targets for developing novel antibiofilm therapeutics. Their activities often depend on protein–protein interactions. Therefore, such targets present unique opportunities and challenges to drug discovery. In Bacillus subtilis, a model organism for studying biofilms, SinR acts as the master regulator of the biofilm formation cascade. Under favourable growth conditions, it represses the epsA-O and tapA-sipW-tasA operons, which encode for essential structural components of biofilms. Under unfavourable growth conditions, SinI, an agonist protein, inactivates SinR by forming a heterotrimeric complex. This results in derepression of epsA-O and tapA-sipW-tasA operons and leads to the phenotypic switch from planktonic to biofilm-associated form. We hypothesized that inhibiting SinR–SinI interaction might warrant repression of epsA-O and tapA-sipW-tasA operons and inhibit biofilm formation. To evaluate this hypothesis, we carried out a drug repurposing study for identifying potential inhibitors of SinI. Cefoperazone and itraconazole were identified as potential inhibitors with virtual screening. The stability of their interaction with SinI was assessed in extended MD performed over 100 ns. Both cefoperazone and itraconazole showed stable interaction. In in vitro studies, cefoperazone hindered the interaction of purified recombinant SinI and SinR. In the whole cell-based biofilm inhibition assays also cefoperazone was found to efficiently inhibited biofilm formation. These results provide proof of concept for targeting protein–protein interaction of master regulators as potential target for discovery and development of antibiofilm therapeutics. We propose that similar drug repurposing studies targeting key regulators of biofilm formation cascade could be an efficient approach for discovering novel anti-biofilm therapeutics against priority pathogens. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. |
| abstractGer |
Abstract Biofilm-associated microbial growth is a major cause of environmental, industrial, and public health concern. Therefore, there is a pressing need to discover and develop efficient antibiofilm strategies. Regulatory proteins vital for biofilm formation might be ideal targets for developing novel antibiofilm therapeutics. Their activities often depend on protein–protein interactions. Therefore, such targets present unique opportunities and challenges to drug discovery. In Bacillus subtilis, a model organism for studying biofilms, SinR acts as the master regulator of the biofilm formation cascade. Under favourable growth conditions, it represses the epsA-O and tapA-sipW-tasA operons, which encode for essential structural components of biofilms. Under unfavourable growth conditions, SinI, an agonist protein, inactivates SinR by forming a heterotrimeric complex. This results in derepression of epsA-O and tapA-sipW-tasA operons and leads to the phenotypic switch from planktonic to biofilm-associated form. We hypothesized that inhibiting SinR–SinI interaction might warrant repression of epsA-O and tapA-sipW-tasA operons and inhibit biofilm formation. To evaluate this hypothesis, we carried out a drug repurposing study for identifying potential inhibitors of SinI. Cefoperazone and itraconazole were identified as potential inhibitors with virtual screening. The stability of their interaction with SinI was assessed in extended MD performed over 100 ns. Both cefoperazone and itraconazole showed stable interaction. In in vitro studies, cefoperazone hindered the interaction of purified recombinant SinI and SinR. In the whole cell-based biofilm inhibition assays also cefoperazone was found to efficiently inhibited biofilm formation. These results provide proof of concept for targeting protein–protein interaction of master regulators as potential target for discovery and development of antibiofilm therapeutics. We propose that similar drug repurposing studies targeting key regulators of biofilm formation cascade could be an efficient approach for discovering novel anti-biofilm therapeutics against priority pathogens. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. |
| abstract_unstemmed |
Abstract Biofilm-associated microbial growth is a major cause of environmental, industrial, and public health concern. Therefore, there is a pressing need to discover and develop efficient antibiofilm strategies. Regulatory proteins vital for biofilm formation might be ideal targets for developing novel antibiofilm therapeutics. Their activities often depend on protein–protein interactions. Therefore, such targets present unique opportunities and challenges to drug discovery. In Bacillus subtilis, a model organism for studying biofilms, SinR acts as the master regulator of the biofilm formation cascade. Under favourable growth conditions, it represses the epsA-O and tapA-sipW-tasA operons, which encode for essential structural components of biofilms. Under unfavourable growth conditions, SinI, an agonist protein, inactivates SinR by forming a heterotrimeric complex. This results in derepression of epsA-O and tapA-sipW-tasA operons and leads to the phenotypic switch from planktonic to biofilm-associated form. We hypothesized that inhibiting SinR–SinI interaction might warrant repression of epsA-O and tapA-sipW-tasA operons and inhibit biofilm formation. To evaluate this hypothesis, we carried out a drug repurposing study for identifying potential inhibitors of SinI. Cefoperazone and itraconazole were identified as potential inhibitors with virtual screening. The stability of their interaction with SinI was assessed in extended MD performed over 100 ns. Both cefoperazone and itraconazole showed stable interaction. In in vitro studies, cefoperazone hindered the interaction of purified recombinant SinI and SinR. In the whole cell-based biofilm inhibition assays also cefoperazone was found to efficiently inhibited biofilm formation. These results provide proof of concept for targeting protein–protein interaction of master regulators as potential target for discovery and development of antibiofilm therapeutics. We propose that similar drug repurposing studies targeting key regulators of biofilm formation cascade could be an efficient approach for discovering novel anti-biofilm therapeutics against priority pathogens. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. |
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| title_short |
Efficient Inhibition of Bacterial Biofilm Through Interference of Protein–Protein Interaction of Master Regulator Proteins: a Proof of Concept Study with SinR- SinI Complex of Bacillus subtilis |
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https://dx.doi.org/10.1007/s12010-022-04231-w |
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Pandey, Janmejay |
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| score |
7.400817 |