Host-dependent resistance of Group A Streptococcus to sulfamethoxazole mediated by a horizontally-acquired reduced folate transporter

M. Kalindu D. Rodrigo; Aarti Saiganesh; Andrew J. Hayes; Alisha M. Wilson; Jack Anstey; Janessa L. Pickering; Jua Iwasaki; Jessica Hillas; Scott Winslow; Tabitha Woodman; Philipp Nitschke; Jake A. Lacey; Karen J. Breese; Mark P.G. van der Linden; Philip M. Giffard; Steven Y.C. Tong; Nicola Gray; Keith A. Stubbs; Jonathan R. Carapetis; Asha C. Bowen; Mark R. Davies; Timothy C. Barnett

doi:10.1038/s41467-022-34243-3

Host-dependent resistance of Group A Streptococcus to sulfamethoxazole mediated by a horizontally-acquired reduced folate transporter

M. Kalindu D. Rodrigo, Aarti Saiganesh, Andrew J. Hayes, Alisha M. Wilson, Jack Anstey, Janessa L. Pickering, Jua Iwasaki, Jessica Hillas, Scott Winslow, Tabitha Woodman, Philipp Nitschke, Jake A. Lacey, Karen J. Breese, Mark P.G. van der Linden, Philip M. Giffard, Steven Y.C. Tong, Nicola Gray, Keith A. Stubbs, Jonathan R. Carapetis, Asha C. BowenMark R. Davies, Timothy C. Barnett

Global and Tropical Health

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Abstract

Described antimicrobial resistance mechanisms enable bacteria to avoid the direct effects of antibiotics and can be monitored by in vitro susceptibility testing and genetic methods. Here we describe a mechanism of sulfamethoxazole resistance that requires a host metabolite for activity. Using a combination of in vitro evolution and metabolic rescue experiments, we identify an energy-coupling factor (ECF) transporter S component gene (thfT) that enables Group A Streptococcus to acquire extracellular reduced folate compounds. ThfT likely expands the substrate specificity of an endogenous ECF transporter to acquire reduced folate compounds directly from the host, thereby bypassing the inhibition of folate biosynthesis by sulfamethoxazole. As such, ThfT is a functional equivalent of eukaryotic folate uptake pathways that confers very high levels of resistance to sulfamethoxazole, yet remains undetectable when Group A Streptococcus is grown in the absence of reduced folates. Our study highlights the need to understand how antibiotic susceptibility of pathogens might function during infections to identify additional mechanisms of resistance and reduce ineffective antibiotic use and treatment failures, which in turn further contribute to the spread of antimicrobial resistance genes amongst bacterial pathogens.

Original language	English
Article number	6557
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-34243-3
Publication status	Published - Dec 2022

Bibliographical note

Funding Information:
We thank Manfred Rohde and Mark Walker for providing bacterial strains, Caitlyn Richworth and Jana Haasbroek for help with experiments, Steve McMaster for supplying reagents, Jean Lee and Ben Howden for providing the gradient agar plate method, Ritika Kar Bahal and Mark Nicol for help with photographing agar plates, and Julie Marsh for statistics advice. Some figure panels were created with Biorender.com. This work was supported by the National Health and Medical Research Council grants 1131932 (JRC), 1145033 (SYCT) and 1165876 (MRD), Western Australia Child Research Fund round 8 (TCB), Telethon Perth Children’s Hospital Research Fund round 6 (TCB), Wesfarmers Centre of Vaccines and Infectious Diseases (TCB). TCB is supported by a fellowship from the Western Australian Future Health & Innovation Fund and was previously supported by the Australian National Health and Medical Research Council (NHMRC)-funded ‘Improving Health Outcomes in the Tropical North: A multidisciplinary collaboration (HOT NORTH)’, grant 1131932. MRD is supported by the University of Melbourne CR Roper Fellowship.

Publisher Copyright:
© 2022, The Author(s).

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Rodrigo, M. K. D., Saiganesh, A., Hayes, A. J., Wilson, A. M., Anstey, J., Pickering, J. L., Iwasaki, J., Hillas, J., Winslow, S., Woodman, T., Nitschke, P., Lacey, J. A., Breese, K. J., van der Linden, M. P. G., Giffard, P. M., Tong, S. Y. C., Gray, N., Stubbs, K. A., Carapetis, J. R., ... Barnett, T. C. (2022). Host-dependent resistance of Group A Streptococcus to sulfamethoxazole mediated by a horizontally-acquired reduced folate transporter. Nature Communications, 13(1), Article 6557. https://doi.org/10.1038/s41467-022-34243-3

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title = "Host-dependent resistance of Group A Streptococcus to sulfamethoxazole mediated by a horizontally-acquired reduced folate transporter",

abstract = "Described antimicrobial resistance mechanisms enable bacteria to avoid the direct effects of antibiotics and can be monitored by in vitro susceptibility testing and genetic methods. Here we describe a mechanism of sulfamethoxazole resistance that requires a host metabolite for activity. Using a combination of in vitro evolution and metabolic rescue experiments, we identify an energy-coupling factor (ECF) transporter S component gene (thfT) that enables Group A Streptococcus to acquire extracellular reduced folate compounds. ThfT likely expands the substrate specificity of an endogenous ECF transporter to acquire reduced folate compounds directly from the host, thereby bypassing the inhibition of folate biosynthesis by sulfamethoxazole. As such, ThfT is a functional equivalent of eukaryotic folate uptake pathways that confers very high levels of resistance to sulfamethoxazole, yet remains undetectable when Group A Streptococcus is grown in the absence of reduced folates. Our study highlights the need to understand how antibiotic susceptibility of pathogens might function during infections to identify additional mechanisms of resistance and reduce ineffective antibiotic use and treatment failures, which in turn further contribute to the spread of antimicrobial resistance genes amongst bacterial pathogens.",

author = "Rodrigo, {M. Kalindu D.} and Aarti Saiganesh and Hayes, {Andrew J.} and Wilson, {Alisha M.} and Jack Anstey and Pickering, {Janessa L.} and Jua Iwasaki and Jessica Hillas and Scott Winslow and Tabitha Woodman and Philipp Nitschke and Lacey, {Jake A.} and Breese, {Karen J.} and {van der Linden}, {Mark P.G.} and Giffard, {Philip M.} and Tong, {Steven Y.C.} and Nicola Gray and Stubbs, {Keith A.} and Carapetis, {Jonathan R.} and Bowen, {Asha C.} and Davies, {Mark R.} and Barnett, {Timothy C.}",

note = "Funding Information: We thank Manfred Rohde and Mark Walker for providing bacterial strains, Caitlyn Richworth and Jana Haasbroek for help with experiments, Steve McMaster for supplying reagents, Jean Lee and Ben Howden for providing the gradient agar plate method, Ritika Kar Bahal and Mark Nicol for help with photographing agar plates, and Julie Marsh for statistics advice. Some figure panels were created with Biorender.com. This work was supported by the National Health and Medical Research Council grants 1131932 (JRC), 1145033 (SYCT) and 1165876 (MRD), Western Australia Child Research Fund round 8 (TCB), Telethon Perth Children{\textquoteright}s Hospital Research Fund round 6 (TCB), Wesfarmers Centre of Vaccines and Infectious Diseases (TCB). TCB is supported by a fellowship from the Western Australian Future Health & Innovation Fund and was previously supported by the Australian National Health and Medical Research Council (NHMRC)-funded {\textquoteleft}Improving Health Outcomes in the Tropical North: A multidisciplinary collaboration (HOT NORTH){\textquoteright}, grant 1131932. MRD is supported by the University of Melbourne CR Roper Fellowship. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-34243-3",

language = "English",

volume = "13",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

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Rodrigo, MKD, Saiganesh, A, Hayes, AJ, Wilson, AM, Anstey, J, Pickering, JL, Iwasaki, J, Hillas, J, Winslow, S, Woodman, T, Nitschke, P, Lacey, JA, Breese, KJ, van der Linden, MPG, Giffard, PM, Tong, SYC, Gray, N, Stubbs, KA, Carapetis, JR, Bowen, AC, Davies, MR & Barnett, TC 2022, 'Host-dependent resistance of Group A Streptococcus to sulfamethoxazole mediated by a horizontally-acquired reduced folate transporter', Nature Communications, vol. 13, no. 1, 6557. https://doi.org/10.1038/s41467-022-34243-3

TY - JOUR

T1 - Host-dependent resistance of Group A Streptococcus to sulfamethoxazole mediated by a horizontally-acquired reduced folate transporter

AU - Rodrigo, M. Kalindu D.

AU - Saiganesh, Aarti

AU - Hayes, Andrew J.

AU - Wilson, Alisha M.

AU - Anstey, Jack

AU - Pickering, Janessa L.

AU - Iwasaki, Jua

AU - Hillas, Jessica

AU - Winslow, Scott

AU - Woodman, Tabitha

AU - Nitschke, Philipp

AU - Lacey, Jake A.

AU - Breese, Karen J.

AU - van der Linden, Mark P.G.

AU - Giffard, Philip M.

AU - Tong, Steven Y.C.

AU - Gray, Nicola

AU - Stubbs, Keith A.

AU - Carapetis, Jonathan R.

AU - Bowen, Asha C.

AU - Davies, Mark R.

AU - Barnett, Timothy C.

N1 - Funding Information: We thank Manfred Rohde and Mark Walker for providing bacterial strains, Caitlyn Richworth and Jana Haasbroek for help with experiments, Steve McMaster for supplying reagents, Jean Lee and Ben Howden for providing the gradient agar plate method, Ritika Kar Bahal and Mark Nicol for help with photographing agar plates, and Julie Marsh for statistics advice. Some figure panels were created with Biorender.com. This work was supported by the National Health and Medical Research Council grants 1131932 (JRC), 1145033 (SYCT) and 1165876 (MRD), Western Australia Child Research Fund round 8 (TCB), Telethon Perth Children’s Hospital Research Fund round 6 (TCB), Wesfarmers Centre of Vaccines and Infectious Diseases (TCB). TCB is supported by a fellowship from the Western Australian Future Health & Innovation Fund and was previously supported by the Australian National Health and Medical Research Council (NHMRC)-funded ‘Improving Health Outcomes in the Tropical North: A multidisciplinary collaboration (HOT NORTH)’, grant 1131932. MRD is supported by the University of Melbourne CR Roper Fellowship. Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - Described antimicrobial resistance mechanisms enable bacteria to avoid the direct effects of antibiotics and can be monitored by in vitro susceptibility testing and genetic methods. Here we describe a mechanism of sulfamethoxazole resistance that requires a host metabolite for activity. Using a combination of in vitro evolution and metabolic rescue experiments, we identify an energy-coupling factor (ECF) transporter S component gene (thfT) that enables Group A Streptococcus to acquire extracellular reduced folate compounds. ThfT likely expands the substrate specificity of an endogenous ECF transporter to acquire reduced folate compounds directly from the host, thereby bypassing the inhibition of folate biosynthesis by sulfamethoxazole. As such, ThfT is a functional equivalent of eukaryotic folate uptake pathways that confers very high levels of resistance to sulfamethoxazole, yet remains undetectable when Group A Streptococcus is grown in the absence of reduced folates. Our study highlights the need to understand how antibiotic susceptibility of pathogens might function during infections to identify additional mechanisms of resistance and reduce ineffective antibiotic use and treatment failures, which in turn further contribute to the spread of antimicrobial resistance genes amongst bacterial pathogens.

AB - Described antimicrobial resistance mechanisms enable bacteria to avoid the direct effects of antibiotics and can be monitored by in vitro susceptibility testing and genetic methods. Here we describe a mechanism of sulfamethoxazole resistance that requires a host metabolite for activity. Using a combination of in vitro evolution and metabolic rescue experiments, we identify an energy-coupling factor (ECF) transporter S component gene (thfT) that enables Group A Streptococcus to acquire extracellular reduced folate compounds. ThfT likely expands the substrate specificity of an endogenous ECF transporter to acquire reduced folate compounds directly from the host, thereby bypassing the inhibition of folate biosynthesis by sulfamethoxazole. As such, ThfT is a functional equivalent of eukaryotic folate uptake pathways that confers very high levels of resistance to sulfamethoxazole, yet remains undetectable when Group A Streptococcus is grown in the absence of reduced folates. Our study highlights the need to understand how antibiotic susceptibility of pathogens might function during infections to identify additional mechanisms of resistance and reduce ineffective antibiotic use and treatment failures, which in turn further contribute to the spread of antimicrobial resistance genes amongst bacterial pathogens.

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U2 - 10.1038/s41467-022-34243-3

DO - 10.1038/s41467-022-34243-3

M3 - Article

C2 - 36450721

AN - SCOPUS:85143112427

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

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ER -

Host-dependent resistance of Group A Streptococcus to sulfamethoxazole mediated by a horizontally-acquired reduced folate transporter

Abstract

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