Bacteria use a variety of mechanisms to render antimicrobials ineffective: efflux pumps that remove compounds from the cell, enzymatic degradation of an antimicrobial compound, and modification of a target are some examples that are widely used. These well-described antimicrobial resistance (AMR) mechanisms can be monitored by in vitro susceptibility testing and genetic methods.

Now, a new form of AMR—one that is undetectable using traditional laboratory testing methods—has been uncovered. The mechanism, which requires a host metabolite for activity, enables Group A Streptococcus to take up nutrients from their human host and confer sulfamethoxazole resistance. More specifically, the bacteria acquire extracellular reduced folate compounds directly from the host in order to bypass the inhibition of folate biosynthesis by sulfamethoxazole.

This study is published in Nature Communications, in the paper, “Host-dependent resistance of Group A Streptococcus to sulfamethoxazole mediated by a horizontally-acquired reduced folate transporter.”

“AMR is a silent pandemic of much greater risk to society than COVID-19. In addition to 10 million deaths per year by 2050, the World Health Organization estimates AMR will cost the global economy $100 trillion if we can’t find a way to combat antibiotic failure,” said Timothy Barnett, PhD, head of the Strep A pathogenesis and diagnostics team at the Wesfarmers Centre of Vaccines and Infectious Diseases, based at Telethon Kids Institute in Perth, Western Australia.

“Without antibiotics, we face a world where there will be no way to stop deadly infections,” Barnett continued. “Cancer patients won’t be able to have chemotherapy and people won’t have access to life-saving surgeries. In order to preserve the long-term efficacy of antibiotics, we need to further identify and understand new mechanisms of antibiotic resistance, which will aid in the discovery of new antibiotics and allow us to monitor AMR as it arises.”

Bacteria need to make their own folates to grow. Some antibiotics work by blocking folate production, which stops bacterial growth.

When studying an antibiotic commonly prescribed to treat Group A Strep skin infections, sulfamethoxazole, the researchers used a combination of in vitro evolution and metabolic rescue experiments to identify the mechanism of resistance where, for the first time ever, the bacteria demonstrated the ability to take folates directly from their human host when blocked from producing their own.

More specifically, the findings identify an energy-coupling factor (ECF) transporter S component gene (thfT) that enables Group A Streptococcus to acquire extracellular reduced folate compounds. ThfT, they note, 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.”

The authors continued that “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.”

Because the new form of resistance is undetectable under conditions routinely used in pathology laboratories, it is very hard for clinicians to prescribe antibiotics that will effectively treat the infection, potentially leading to very poor outcomes and even premature death.

“Unfortunately, we suspect this is just the tip of the iceberg,” noted Barnett. “We have identified this mechanism in Group A Strep but it’s likely it will be a broader issue across other bacterial pathogens.”

The team will now focus on developing testing methods to detect this antibiotic resistance mechanism to enable effective treatment.

“It is vital we stay one step ahead of the challenges of AMR and, as researchers, we should continue to explore how resistance develops in pathogens and design rapid accurate diagnostic methods and therapeutics,” noted Kalindu Rodrigo, a PhD student in the Barnett lab. “On the other hand, equal efforts should be taken at all levels of the society including patients, health professionals, and policymakers to help reduce the impacts of AMR.”

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