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

MKD Rodrigo; A Saiganesh; AJ Hayes; AM Wilson; J Anstey; JL Pickering; J Iwasaki; J Hillas; S Winslow; T Woodman; P Nitschke; JA Lacey; KJ Breese; MPG van der Linden; PM Giffard; SYC Tong; N Gray; KA Stubbs; JR Carapetis; AC Bowen; MR Davies; TC Barnett

Journal article

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

MKD Rodrigo, A Saiganesh, AJ Hayes, AM Wilson, J Anstey, JL Pickering, J Iwasaki, J Hillas, S Winslow, T Woodman, P Nitschke, JA Lacey, KJ Breese, MPG van der Linden, PM Giffard, SYC Tong, N Gray, KA Stubbs, JR Carapetis, AC Bowen Show all

Nature Communications | Published : 2022

DOI: 10.1038/s41467-022-34243-3

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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 inhibitio..

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Awarded by National Health and Medical Research Council

Funding Acknowledgements

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 andMark 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 theWestern 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.