Targeting Mannitol Metabolism as an Alternative Antimicrobial Strategy Based on the Structure-Function Study of Mannitol-1-Phosphate Dehydrogenase in <named-content content-type="genus-species">Staphylococcus aureus</named-content>

ABSTRACT Mannitol-1-phosphate dehydrogenase (M1PDH) is a key enzyme in Staphylococcus aureus mannitol metabolism, but its roles in pathophysiological settings have not been established. We performed comprehensive structure-function analysis of M1PDH from S. aureus USA300, a strain of community-assoc...

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Autores principales:	Thanh Nguyen, Truc Kim, Hai Minh Ta, Won Sik Yeo, Jongkeun Choi, Pushpak Mizar, Seung Seo Lee, Taeok Bae, Akhilesh Kumar Chaurasia, Kyeong Kyu Kim
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	mannitol-1-phosphate dehydrogenase Staphylococcus aureus antibiotic target antimicrobial resistance crystal structure inhibitor Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/c59721ba0d04422397540abf716cd3c0
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spelling	oai:doaj.org-article:c59721ba0d04422397540abf716cd3c02021-11-15T16:22:10ZTargeting Mannitol Metabolism as an Alternative Antimicrobial Strategy Based on the Structure-Function Study of Mannitol-1-Phosphate Dehydrogenase in <named-content content-type="genus-species">Staphylococcus aureus</named-content>10.1128/mBio.02660-182150-7511https://doaj.org/article/c59721ba0d04422397540abf716cd3c02019-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02660-18https://doaj.org/toc/2150-7511ABSTRACT Mannitol-1-phosphate dehydrogenase (M1PDH) is a key enzyme in Staphylococcus aureus mannitol metabolism, but its roles in pathophysiological settings have not been established. We performed comprehensive structure-function analysis of M1PDH from S. aureus USA300, a strain of community-associated methicillin-resistant S. aureus, to evaluate its roles in cell viability and virulence under pathophysiological conditions. On the basis of our results, we propose M1PDH as a potential antibacterial target. In vitro cell viability assessment of ΔmtlD knockout and complemented strains confirmed that M1PDH is essential to endure pH, high-salt, and oxidative stress and thus that M1PDH is required for preventing osmotic burst by regulating pressure potential imposed by mannitol. The mouse infection model also verified that M1PDH is essential for bacterial survival during infection. To further support the use of M1PDH as an antibacterial target, we identified dihydrocelastrol (DHCL) as a competitive inhibitor of S. aureus M1PDH (SaM1PDH) and confirmed that DHCL effectively reduces bacterial cell viability during host infection. To explain physiological functions of SaM1PDH at the atomic level, the crystal structure of SaM1PDH was determined at 1.7-Å resolution. Structure-based mutation analyses and DHCL molecular docking to the SaM1PDH active site followed by functional assay identified key residues in the active site and provided the action mechanism of DHCL. Collectively, we propose SaM1PDH as a target for antibiotic development based on its physiological roles with the goals of expanding the repertory of antibiotic targets to fight antimicrobial resistance and providing essential knowledge for developing potent inhibitors of SaM1PDH based on structure-function studies. IMPORTANCE Due to the shortage of effective antibiotics against drug-resistant Staphylococcus aureus, new targets are urgently required to develop next-generation antibiotics. We investigated mannitol-1-phosphate dehydrogenase of S. aureus USA300 (SaM1PDH), a key enzyme regulating intracellular mannitol levels, and explored the possibility of using SaM1PDH as a target for developing antibiotic. Since mannitol is necessary for maintaining the cellular redox and osmotic potential, the homeostatic imbalance caused by treatment with a SaM1PDH inhibitor or knockout of the gene encoding SaM1PDH results in bacterial cell death through oxidative and/or mannitol-dependent cytolysis. We elucidated the molecular mechanism of SaM1PDH and the structural basis of substrate and inhibitor recognition by enzymatic and structural analyses of SaM1PDH. Our results strongly support the concept that targeting of SaM1PDH represents an alternative strategy for developing a new class of antibiotics that cause bacterial cell death not by blocking key cellular machinery but by inducing cytolysis and reducing stress tolerance through inhibition of the mannitol pathway.Thanh NguyenTruc KimHai Minh TaWon Sik YeoJongkeun ChoiPushpak MizarSeung Seo LeeTaeok BaeAkhilesh Kumar ChaurasiaKyeong Kyu KimAmerican Society for Microbiologyarticlemannitol-1-phosphate dehydrogenaseStaphylococcus aureusantibiotic targetantimicrobial resistancecrystal structureinhibitorMicrobiologyQR1-502ENmBio, Vol 10, Iss 4 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	mannitol-1-phosphate dehydrogenase Staphylococcus aureus antibiotic target antimicrobial resistance crystal structure inhibitor Microbiology QR1-502
spellingShingle	mannitol-1-phosphate dehydrogenase Staphylococcus aureus antibiotic target antimicrobial resistance crystal structure inhibitor Microbiology QR1-502 Thanh Nguyen Truc Kim Hai Minh Ta Won Sik Yeo Jongkeun Choi Pushpak Mizar Seung Seo Lee Taeok Bae Akhilesh Kumar Chaurasia Kyeong Kyu Kim Targeting Mannitol Metabolism as an Alternative Antimicrobial Strategy Based on the Structure-Function Study of Mannitol-1-Phosphate Dehydrogenase in <named-content content-type="genus-species">Staphylococcus aureus</named-content>
description	ABSTRACT Mannitol-1-phosphate dehydrogenase (M1PDH) is a key enzyme in Staphylococcus aureus mannitol metabolism, but its roles in pathophysiological settings have not been established. We performed comprehensive structure-function analysis of M1PDH from S. aureus USA300, a strain of community-associated methicillin-resistant S. aureus, to evaluate its roles in cell viability and virulence under pathophysiological conditions. On the basis of our results, we propose M1PDH as a potential antibacterial target. In vitro cell viability assessment of ΔmtlD knockout and complemented strains confirmed that M1PDH is essential to endure pH, high-salt, and oxidative stress and thus that M1PDH is required for preventing osmotic burst by regulating pressure potential imposed by mannitol. The mouse infection model also verified that M1PDH is essential for bacterial survival during infection. To further support the use of M1PDH as an antibacterial target, we identified dihydrocelastrol (DHCL) as a competitive inhibitor of S. aureus M1PDH (SaM1PDH) and confirmed that DHCL effectively reduces bacterial cell viability during host infection. To explain physiological functions of SaM1PDH at the atomic level, the crystal structure of SaM1PDH was determined at 1.7-Å resolution. Structure-based mutation analyses and DHCL molecular docking to the SaM1PDH active site followed by functional assay identified key residues in the active site and provided the action mechanism of DHCL. Collectively, we propose SaM1PDH as a target for antibiotic development based on its physiological roles with the goals of expanding the repertory of antibiotic targets to fight antimicrobial resistance and providing essential knowledge for developing potent inhibitors of SaM1PDH based on structure-function studies. IMPORTANCE Due to the shortage of effective antibiotics against drug-resistant Staphylococcus aureus, new targets are urgently required to develop next-generation antibiotics. We investigated mannitol-1-phosphate dehydrogenase of S. aureus USA300 (SaM1PDH), a key enzyme regulating intracellular mannitol levels, and explored the possibility of using SaM1PDH as a target for developing antibiotic. Since mannitol is necessary for maintaining the cellular redox and osmotic potential, the homeostatic imbalance caused by treatment with a SaM1PDH inhibitor or knockout of the gene encoding SaM1PDH results in bacterial cell death through oxidative and/or mannitol-dependent cytolysis. We elucidated the molecular mechanism of SaM1PDH and the structural basis of substrate and inhibitor recognition by enzymatic and structural analyses of SaM1PDH. Our results strongly support the concept that targeting of SaM1PDH represents an alternative strategy for developing a new class of antibiotics that cause bacterial cell death not by blocking key cellular machinery but by inducing cytolysis and reducing stress tolerance through inhibition of the mannitol pathway.
format	article
author	Thanh Nguyen Truc Kim Hai Minh Ta Won Sik Yeo Jongkeun Choi Pushpak Mizar Seung Seo Lee Taeok Bae Akhilesh Kumar Chaurasia Kyeong Kyu Kim
author_facet	Thanh Nguyen Truc Kim Hai Minh Ta Won Sik Yeo Jongkeun Choi Pushpak Mizar Seung Seo Lee Taeok Bae Akhilesh Kumar Chaurasia Kyeong Kyu Kim
author_sort	Thanh Nguyen
title	Targeting Mannitol Metabolism as an Alternative Antimicrobial Strategy Based on the Structure-Function Study of Mannitol-1-Phosphate Dehydrogenase in <named-content content-type="genus-species">Staphylococcus aureus</named-content>
title_short	Targeting Mannitol Metabolism as an Alternative Antimicrobial Strategy Based on the Structure-Function Study of Mannitol-1-Phosphate Dehydrogenase in <named-content content-type="genus-species">Staphylococcus aureus</named-content>
title_full	Targeting Mannitol Metabolism as an Alternative Antimicrobial Strategy Based on the Structure-Function Study of Mannitol-1-Phosphate Dehydrogenase in <named-content content-type="genus-species">Staphylococcus aureus</named-content>
title_fullStr	Targeting Mannitol Metabolism as an Alternative Antimicrobial Strategy Based on the Structure-Function Study of Mannitol-1-Phosphate Dehydrogenase in <named-content content-type="genus-species">Staphylococcus aureus</named-content>
title_full_unstemmed	Targeting Mannitol Metabolism as an Alternative Antimicrobial Strategy Based on the Structure-Function Study of Mannitol-1-Phosphate Dehydrogenase in <named-content content-type="genus-species">Staphylococcus aureus</named-content>
title_sort	targeting mannitol metabolism as an alternative antimicrobial strategy based on the structure-function study of mannitol-1-phosphate dehydrogenase in <named-content content-type="genus-species">staphylococcus aureus</named-content>
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/c59721ba0d04422397540abf716cd3c0
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Targeting Mannitol Metabolism as an Alternative Antimicrobial Strategy Based on the Structure-Function Study of Mannitol-1-Phosphate Dehydrogenase in <named-content content-type="genus-species">Staphylococcus aureus</named-content>

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