Stable antibiotic resistance and rapid human adaptation in livestock-associated MRSA

Abstract

Mobile genetic elements (MGEs) are agents of horizontal gene transfer in bacteria, but can also be vertically inherited by daughter cells. Establishing the dynamics that led to contemporary patterns of MGEs in bacterial genomes is central to predicting the emergence and evolution of novel and resistant pathogens. Methicillin-resistant Staphylococcus aureus (MRSA) clonal-complex (CC) 398 is the dominant MRSA in European livestock and a growing cause of human infections. Previous studies have identified three categories of MGEs whose presence or absence distinguishes livestock-associated CC398 from a closely related and less antibiotic-resistant human-associated population. Here, we fully characterise the evolutionary dynamics of these MGEs using a collection of 1180 CC398 genomes, sampled from livestock and humans, over 27 years. We find that the emergence of livestock-associated CC398 coincided with the acquisition of a Tn 916 transposon carrying a tetracycline resistance gene, which has been stably inherited for 57 years. This was followed by the acquisition of a type V SCC mec that carries methicillin, tetracycline, and heavy metal resistance genes, which has been maintained for 35 years, with occasional truncations and replacements with type IV SCC mec. In contrast, a class of prophages that carry a human immune evasion gene cluster and that are largely absent from livestock-associated CC398 have been repeatedly gained and lost in both human- and livestock-associated CC398. These contrasting dynamics mean that when livestock-associated MRSA is transmitted to humans, adaptation to the human host outpaces loss of antibiotic resistance. In addition, the stable inheritance of resistance-associated MGEs suggests that the impact of ongoing reductions in antibiotic and zinc oxide use in European farms on livestock-associated MRSA will be slow to be realised.

eLife digest

Antibiotic-resistant infections are a growing threat to human health. In 2019, these hard-to-treat infections resulted in 4.95 million deaths making them the third leading cause of death that year. Excessive use of antibiotics in humans is likely driving the emergence of drug-resistant bacteria. But there is a concern that use of antibiotics on livestock farms is also contributing. A type of bacteria traced back to livestock is a growing cause of human infections that do not respond to treatment with the antibiotic methicillin in Europe. It is called livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA).

Bacteria can share genes that make them drug resistant or more deadly. These genes are often carried on mobile genetic elements that promote their movement from one bacterial cell to another. The most common type of LA-MRSA in Europe is clonal-complex 398 (CC398). It has two mobile genetic elements carrying antibiotic-resistance genes, but generally lacks a mobile genetic element that helps the bacterium escape the human immune system. Learning more about how LA-MRSA acquired these genetic changes may help scientists develop better strategies to protect the public.

Matuszewska, Murray et al. analyzed the genomes of more than 1,000 samples of CC398 collected from humans, pigs and 13 other animal species in 28 countries over 27 years. They used this data to reconstruct the bacteria’s evolutionary history. Matuszewska, Murray et al. show that two mobile elements containing antibiotic resistance genes in CC398 were gained decades ago. One is more than 50 years old and was likely acquired around the time antibiotic use in livestock became common. While most CC398 in livestock do not have a mobile element that helps LA-MRSA evade the human immune system, they often gain it when they infect humans. This leads to highly drug-resistant human MRSA infections.

The results of this study suggest that LA-MRSA is a serious threat to human health. The resistance of this bacterium has persisted for decades, spreading across different livestock species and different countries. These drug-resistant bacteria in livestock readily infect humans. Current efforts to reduce antibiotic use in farms may take decades to mitigate these risks. Additionally, the ban on zinc-oxide use on livestock in the European Union (coming into force June 2022) may not help reduce LA-MRSA, because the genes conferring resistance to bacteria and zinc treatment are not always linked.