Tomatidine Is a Lead Antibiotic Molecule That Targets Staphylococcus aureus ATP Synthase Subunit C
Methicillin-resistant (MRSA) is a leading cause of deadly hospital-acquired infections. The discovery of anti- antibiotics and new classes of drugs not susceptible to the mechanisms of resistance shared among bacteria is imperative. We recently showed that tomatidine (TO), a steroidal alkaloid from...
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| Published in: | Antimicrobial agents and chemotherapy Vol. 62; no. 6 |
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| Main Authors: | , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
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American Society for Microbiology
01-06-2018
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| Abstract | Methicillin-resistant
(MRSA) is a leading cause of deadly hospital-acquired infections. The discovery of anti-
antibiotics and new classes of drugs not susceptible to the mechanisms of resistance shared among bacteria is imperative. We recently showed that tomatidine (TO), a steroidal alkaloid from solanaceous plants, possesses potent antibacterial activity against
small-colony variants (SCVs), the notoriously persistent form of this bacterium that has been associated with recurrence of infections. Here, using genomic analysis of
-generated TO-resistant
strains to identify mutations in genes involved in resistance, we identified the bacterial ATP synthase as the cellular target. Sequence alignments were performed to highlight the modified sequences, and the structural consequences of the mutations were evaluated in structural models. Overexpression of the
gene in
SCVs or introducing the mutation found in the
gene of one of the high-level TO-resistant
mutants into the
gene provided resistance to TO and further validated the identity of the cellular target. FC04-100, a TO derivative which also possesses activity against non-SCV strains, prevents high-level resistance development in prototypic strains and limits the level of resistance observed in SCVs. An ATP synthesis assay allowed the observation of a correlation between antibiotic potency and ATP synthase inhibition. The selectivity index (inhibition of ATP production by mitochondria versus that of bacterial ATP synthase) is estimated to be >10
-fold for FC04-100. |
|---|---|
| AbstractList | Methicillin-resistant
Staphylococcus aureus
(MRSA) is a leading cause of deadly hospital-acquired infections. The discovery of anti-
Staphylococcus
antibiotics and new classes of drugs not susceptible to the mechanisms of resistance shared among bacteria is imperative. We recently showed that tomatidine (TO), a steroidal alkaloid from solanaceous plants, possesses potent antibacterial activity against
S. aureus
small-colony variants (SCVs), the notoriously persistent form of this bacterium that has been associated with recurrence of infections. Here, using genomic analysis of
in vitro
-generated TO-resistant
S. aureus
strains to identify mutations in genes involved in resistance, we identified the bacterial ATP synthase as the cellular target. Sequence alignments were performed to highlight the modified sequences, and the structural consequences of the mutations were evaluated in structural models. Overexpression of the
atpE
gene in
S. aureus
SCVs or introducing the mutation found in the
atpE
gene of one of the high-level TO-resistant
S. aureus
mutants into the
Bacillus subtilis atpE
gene provided resistance to TO and further validated the identity of the cellular target. FC04-100, a TO derivative which also possesses activity against non-SCV strains, prevents high-level resistance development in prototypic strains and limits the level of resistance observed in SCVs. An ATP synthesis assay allowed the observation of a correlation between antibiotic potency and ATP synthase inhibition. The selectivity index (inhibition of ATP production by mitochondria versus that of bacterial ATP synthase) is estimated to be >10
5
-fold for FC04-100. Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of deadly hospital-acquired infections. The discovery of anti-Staphylococcus antibiotics and new classes of drugs not susceptible to the mechanisms of resistance shared among bacteria is imperative. We recently showed that tomatidine (TO), a steroidal alkaloid from solanaceous plants, possesses potent antibacterial activity against S. aureus small-colony variants (SCVs), the notoriously persistent form of this bacterium that has been associated with recurrence of infections. Here, using genomic analysis of in vitro-generated TO-resistant S. aureus strains to identify mutations in genes involved in resistance, we identified the bacterial ATP synthase as the cellular target. Sequence alignments were performed to highlight the modified sequences, and the structural consequences of the mutations were evaluated in structural models. Overexpression of the atpE gene in S. aureus SCVs or introducing the mutation found in the atpE gene of one of the high-level TO-resistant S. aureus mutants into the Bacillus subtilis atpE gene provided resistance to TO and further validated the identity of the cellular target. FC04-100, a TO derivative which also possesses activity against non-SCV strains, prevents high-level resistance development in prototypic strains and limits the level of resistance observed in SCVs. An ATP synthesis assay allowed the observation of a correlation between antibiotic potency and ATP synthase inhibition. The selectivity index (inhibition of ATP production by mitochondria versus that of bacterial ATP synthase) is estimated to be >105-fold for FC04-100. Methicillin-resistant (MRSA) is a leading cause of deadly hospital-acquired infections. The discovery of anti- antibiotics and new classes of drugs not susceptible to the mechanisms of resistance shared among bacteria is imperative. We recently showed that tomatidine (TO), a steroidal alkaloid from solanaceous plants, possesses potent antibacterial activity against small-colony variants (SCVs), the notoriously persistent form of this bacterium that has been associated with recurrence of infections. Here, using genomic analysis of -generated TO-resistant strains to identify mutations in genes involved in resistance, we identified the bacterial ATP synthase as the cellular target. Sequence alignments were performed to highlight the modified sequences, and the structural consequences of the mutations were evaluated in structural models. Overexpression of the gene in SCVs or introducing the mutation found in the gene of one of the high-level TO-resistant mutants into the gene provided resistance to TO and further validated the identity of the cellular target. FC04-100, a TO derivative which also possesses activity against non-SCV strains, prevents high-level resistance development in prototypic strains and limits the level of resistance observed in SCVs. An ATP synthesis assay allowed the observation of a correlation between antibiotic potency and ATP synthase inhibition. The selectivity index (inhibition of ATP production by mitochondria versus that of bacterial ATP synthase) is estimated to be >10 -fold for FC04-100. Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of deadly hospital-acquired infections. The discovery of anti-Staphylococcus antibiotics and new classes of drugs not susceptible to the mechanisms of resistance shared among bacteria is imperative. We recently showed that tomatidine (TO), a steroidal alkaloid from solanaceous plants, possesses potent antibacterial activity against S. aureus small-colony variants (SCVs), the notoriously persistent form of this bacterium that has been associated with recurrence of infections. Here, using genomic analysis of in vitro-generated TO-resistant S. aureus strains to identify mutations in genes involved in resistance, we identified the bacterial ATP synthase as the cellular target. Sequence alignments were performed to highlight the modified sequences, and the structural consequences of the mutations were evaluated in structural models. Overexpression of the atpE gene in S. aureus SCVs or introducing the mutation found in the atpE gene of one of the high-level TO-resistant S. aureus mutants into the Bacillus subtilis atpE gene provided resistance to TO and further validated the identity of the cellular target. FC04-100, a TO derivative which also possesses activity against non-SCV strains, prevents high-level resistance development in prototypic strains and limits the level of resistance observed in SCVs. An ATP synthesis assay allowed the observation of a correlation between antibiotic potency and ATP synthase inhibition. The selectivity index (inhibition of ATP production by mitochondria versus that of bacterial ATP synthase) is estimated to be >105-fold for FC04-100. |
| Author | Boyapelly, Kumaraswamy Malouin, François Rodrigue, Sébastien Langlois, Jean-Philippe Brzezinski, Ryszard Beauregard, Pascale B Isabelle, Charles Lamontagne Boulet, Maxime Guay, Isabelle Boudreault, Pierre-Luc Brouillette, Eric Bouarab, Kamal Jacques, Pierre-Étienne Marsault, Éric |
| Author_xml | – sequence: 1 givenname: Maxime surname: Lamontagne Boulet fullname: Lamontagne Boulet, Maxime organization: Centre d'Étude et de Valorisation de la Diversité Microbienne, Département de Biologie, Faculté des Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada – sequence: 2 givenname: Charles surname: Isabelle fullname: Isabelle, Charles organization: Centre d'Étude et de Valorisation de la Diversité Microbienne, Département de Biologie, Faculté des Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada – sequence: 3 givenname: Isabelle surname: Guay fullname: Guay, Isabelle organization: Centre d'Étude et de Valorisation de la Diversité Microbienne, Département de Biologie, Faculté des Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada – sequence: 4 givenname: Eric surname: Brouillette fullname: Brouillette, Eric organization: Centre d'Étude et de Valorisation de la Diversité Microbienne, Département de Biologie, Faculté des Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada – sequence: 5 givenname: Jean-Philippe surname: Langlois fullname: Langlois, Jean-Philippe organization: Centre d'Étude et de Valorisation de la Diversité Microbienne, Département de Biologie, Faculté des Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada – sequence: 6 givenname: Pierre-Étienne surname: Jacques fullname: Jacques, Pierre-Étienne organization: Centre d'Étude et de Valorisation de la Diversité Microbienne, Département de Biologie, Faculté des Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada – sequence: 7 givenname: Sébastien surname: Rodrigue fullname: Rodrigue, Sébastien organization: Centre d'Étude et de Valorisation de la Diversité Microbienne, Département de Biologie, Faculté des Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada – sequence: 8 givenname: Ryszard surname: Brzezinski fullname: Brzezinski, Ryszard organization: Centre d'Étude et de Valorisation de la Diversité Microbienne, Département de Biologie, Faculté des Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada – sequence: 9 givenname: Pascale B surname: Beauregard fullname: Beauregard, Pascale B organization: Centre d'Étude et de Valorisation de la Diversité Microbienne, Département de Biologie, Faculté des Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada – sequence: 10 givenname: Kamal surname: Bouarab fullname: Bouarab, Kamal organization: Centre d'Étude et de Valorisation de la Diversité Microbienne, Département de Biologie, Faculté des Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada – sequence: 11 givenname: Kumaraswamy surname: Boyapelly fullname: Boyapelly, Kumaraswamy organization: Département de Pharmacologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Quebec, Canada – sequence: 12 givenname: Pierre-Luc surname: Boudreault fullname: Boudreault, Pierre-Luc organization: Département de Pharmacologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Quebec, Canada – sequence: 13 givenname: Éric surname: Marsault fullname: Marsault, Éric organization: Département de Pharmacologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Quebec, Canada – sequence: 14 givenname: François orcidid: 0000-0001-5031-345X surname: Malouin fullname: Malouin, François email: francois.malouin@usherbrooke.ca organization: Centre d'Étude et de Valorisation de la Diversité Microbienne, Département de Biologie, Faculté des Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada francois.malouin@usherbrooke.ca |
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| ContentType | Journal Article |
| Copyright | Copyright © 2018 American Society for Microbiology. Copyright © 2018 American Society for Microbiology. 2018 American Society for Microbiology |
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| DocumentTitleAlternate | Tomatidine Targets ATP Synthase, Lamontagne Boulet et al Tomatidine Targets ATP Synthase |
| EISSN | 1098-6596 |
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| Issue | 6 |
| Keywords | tomatidine new target small-colony variant ATP synthase Staphylococcus aureus |
| Language | English |
| License | Copyright © 2018 American Society for Microbiology. All Rights Reserved. https://doi.org/10.1128/ASMCopyrightv2 All Rights Reserved. |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Citation Lamontagne Boulet M, Isabelle C, Guay I, Brouillette E, Langlois J-P, Jacques P-É, Rodrigue S, Brzezinski R, Beauregard PB, Bouarab K, Boyapelly K, Boudreault P-L, Marsault É, Malouin F. 2018. Tomatidine is a lead antibiotic molecule that targets Staphylococcus aureus ATP synthase subunit C. Antimicrob Agents Chemother 62:e02197-17. https://doi.org/10.1128/AAC.02197-17. M.L.B., C.I., and I.G. contributed equally to this article. |
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| PublicationTitle | Antimicrobial agents and chemotherapy |
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| Snippet | Methicillin-resistant
(MRSA) is a leading cause of deadly hospital-acquired infections. The discovery of anti-
antibiotics and new classes of drugs not... Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of deadly hospital-acquired infections. The discovery of anti-Staphylococcus antibiotics... Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of deadly hospital-acquired infections. The discovery of anti- Staphylococcus antibiotics... |
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| SubjectTerms | Anti-Bacterial Agents Experimental Therapeutics Mitochondrial Proton-Translocating ATPases Staphylococcus aureus Tomatine |
| Title | Tomatidine Is a Lead Antibiotic Molecule That Targets Staphylococcus aureus ATP Synthase Subunit C |
| URI | https://www.ncbi.nlm.nih.gov/pubmed/29610201 https://journals.asm.org/doi/10.1128/AAC.02197-17 https://search.proquest.com/docview/2021319528 https://pubmed.ncbi.nlm.nih.gov/PMC5971568 |
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