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. Linden, Philip M. Giffard, Steven Y. C. Tong, Nicola Gray, Keith A. Stubbs, Jonathan R. Carapetis, Asha C. Bowen, Mark R. Davies and Timothy C. Barnett ()
Additional contact information
M. Kalindu D. Rodrigo: University of Western Australia
Aarti Saiganesh: University of Western Australia
Andrew J. Hayes: University of Melbourne
Alisha M. Wilson: University of Western Australia
Jack Anstey: University of Western Australia
Janessa L. Pickering: University of Western Australia
Jua Iwasaki: University of Western Australia
Jessica Hillas: University of Western Australia
Scott Winslow: University of Western Australia
Tabitha Woodman: University of Western Australia
Philipp Nitschke: Murdoch University
Jake A. Lacey: University of Melbourne
Karen J. Breese: University of Western Australia
Mark P. G. Linden: University Hospital RWTH Aachen
Philip M. Giffard: Charles Darwin University
Steven Y. C. Tong: University of Melbourne
Nicola Gray: Murdoch University
Keith A. Stubbs: University of Western Australia
Jonathan R. Carapetis: University of Western Australia
Asha C. Bowen: University of Western Australia
Mark R. Davies: University of Melbourne
Timothy C. Barnett: University of Western Australia

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34243-3

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