Researchers have identified a new form of antimicrobial resistance (AMR) in Group A Streptococcus (GAS). GAS organisms can cause various infections that can be minor, like impetigo and strep throat, or highly invasive and deadly, like toxic shock syndrome and necrotising fasciitis. The study, published in Nature Communications, uncovered how GAS could obtain folate nutrients when the biosynthesis pathway was blocked by the antibiotic sulfamethoxazole (SMX).
The AMR threat
AMR is a huge threat to global health and economy. The World Health Organisation estimated that by 2050, 10 million deaths per year will be due to AMR and it will cost the world 100 trillion dollars annually. Bacteria have developed AMR mechanisms in a Darwinian manner. Misuse and overuse of antibiotics has applied the selection pressure to drive the survival of the most well-adapted bacteria. Mechanisms of resistance include reduced membrane permeability, efflux pumps and enzymes that inactivate antibiotics.
The study, led by Dr Timothy Barnett, Head of the Strep A Pathogenesis and Diagnostics team at the Wesfarmers Centre of Vaccines and Infectious Diseases in Western Australia, uncovered a new AMR mechanism in Group A Streptococcus (GAS).
The researchers used in vitro evolution and metabolic rescue experiments to identify the acquisition of a sulfamethoxazole (SMX) resistance gene called energy-coupling factor (ECF) transporter S component (thfT). SMX is an antibiotic that inhibits the synthesis of folates in bacteria. It is used in combination with trimethoprim to treat various infections. This includes community-associated methicillin-resistant Staphylococcus aureus and pneumocystis pneumonia infections.
Dr Barnett said, “When looking at an antibiotic commonly prescribed to treat Group A Strep skin infections, we found a mechanism of resistance where, for the first time ever, the bacteria demonstrated the ability to take folates directly from its human host when blocked from producing their own. This makes the antibiotic ineffective and the infection would likely worsen when the patient should be getting better.”
A new and undetectable AMR mechanism
The SMX resistance protein, encoded by thfT, is a folate transporter. The researchers showed that the transporter allowed GAS to bypass the inhibitory effects of SMX. The bacteria no longer needed the biosynthesis pathway as they were able to acquire folate from their extracellular environment.
The researchers also found that the gene was horizontally acquired (the non-sexual movement of genetic information between genomes). The team analysed datasets of various GAS isolates and probed for thfT sequence homology. They found that the gene was encoded by different GAS sequence types but not across all the strains within a particular sequence type. Horizontal gene transfer of resistance genes means that bacteria can easily transfer AMR to other related Streptococcus species. The study highlighted the importance of monitoring emerging SMX resistance and the need to change the therapeutic approach.
“Unfortunately, we suspect this is just the tip of the iceberg – we have identified this mechanism in Group A Strep, but it’s likely that it will be a broader issue across other bacterial pathogens,” said Dr Barnett.
Since this is a new form of AMR, the researchers investigated detection methods. They found that it could not be detected using tradition laboratory-based antibiotic susceptibility tests. This is because the abundant folate levels seen in hosts cannot be recreated in plate-based assays in the lab. This means that strains carrying thfT could emerge and spread unnoticed by current AMR surveillance methods.
Dr Barnett said, “This new form of resistance is undetectable under conditions routinely used in pathology laboratories, making it very hard for clinicians to prescribe antibiotics that will effectively treat the infection, potentially leading to very poor outcomes and even premature death.”
Future direction
The study shows that new diagnostic tools are required to detect SMX resistance to inform effective treatment. Better surveillance methods, that incorporate genomic methods, are also needed to monitor potential dissemination that may go undetected with tradition lab tests.
Kalindu Rodrigo, first author and PhD student at the University of Western Australia said, “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.”
