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

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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 languageEnglish
Article number6557
JournalNature Communications
Issue number1
Publication statusPublished - 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 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.

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© 2022, The Author(s).


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