Predominance of fabG1 -15C>T in Mycobacterium tuberculosis isolates in Slovenia (2020 – 2024): A Whole genome sequencing study of drug resistance and transmission

Tuberculosis is an ancient bacterial infection that still claims millions of lives worldwide, yet in many places, it has become a manageable condition. The key to managing it lies in understanding the specific strain of the bacteria causing the illness and whether that strain has learned to resist the medicines used to kill it. For decades, doctors relied on growing the bacteria in a lab to see which drugs stopped its growth, a process that takes weeks. Today, scientists can read the bacteria's entire genetic code, a technique called whole-genome sequencing. This method acts like a high-resolution map, allowing researchers to spot tiny changes in the DNA that signal drug resistance and to trace how the bacteria moves from person to person. By comparing these genetic maps, public health officials can distinguish between a new outbreak spreading through a community and old infections waking up from years of dormancy.

In Slovenia, a country where tuberculosis is generally well-controlled, researchers recently turned to this genetic mapping to investigate a specific group of patients diagnosed between 2020 and 2024. They analyzed the genetic code of 342 distinct bacterial samples collected from people with newly diagnosed cases. While the disease remains rare in the general population, it continues to affect specific groups, such as construction workers and residents of social welfare centers. The study aimed to see if the bacteria were resistant to standard treatments, to identify the genetic mutations responsible for that resistance, and to determine if the cases were linked by recent transmission chains.

The investigation revealed that drug resistance was uncommon, appearing in only about 7.6 percent of the cases. Among those resistant cases, the most frequent issue was resistance to isoniazid, a primary drug used to treat tuberculosis. When the researchers looked at the genetic code to find the cause, they discovered a striking pattern. The most common genetic change was a specific alteration in a gene called fabG1. This mutation, which swaps one chemical building block for another at a precise location, was found in nearly 40 percent of the resistant bacteria. This specific change is known to lower the bacteria's ability to be killed by isoniazid and also makes it resistant to ethionamide, a related drug. While other mutations were present, this single genetic shift stood out as the dominant driver of resistance in the region.

The researchers also examined how the bacteria spread. They found that the vast majority of the strains belonged to a family known as lineage 4, which is common across Europe and the world. Within this family, a specific subgroup called Haarlem was the most frequent. The genetic analysis showed that about 19 percent of the cases were likely the result of recent transmission, meaning the bacteria had passed directly from one person to another within the last few years. The remaining cases appeared to be reactivations of old infections or imported from other regions. The study identified several clusters of linked cases, including an outbreak among construction workers and transmission within families, confirming that the bacteria was still moving through specific social networks.

A significant portion of the discussion focused on why the fabG1 mutation was so prevalent. Unlike other common resistance mutations that can weaken the bacteria and make it less fit to survive, this specific change allows the bacteria to resist the drug while maintaining its strength. This suggests that once this mutation appeared in the population, perhaps decades ago, it spread effectively because it did not handicap the bacteria. The researchers noted that this mutation appeared almost exclusively on its own, without other accompanying genetic changes, pointing to a unique local history of transmission. They also found that while most resistant cases were linked to this mutation, a small number of highly resistant cases belonged to a different genetic family, lineage 2, which is often associated with more severe drug resistance globally.

The study concluded that while tuberculosis in Slovenia is largely under control, the genetic landscape of the disease is shaped by specific local dynamics. The dominance of the fabG1 mutation suggests a population-specific pattern of resistance that has evolved and spread within the country. By using whole-genome sequencing, the researchers were able to confirm that the genetic data matched the lab tests for drug resistance in almost every case, with only three minor discrepancies. This high level of agreement validates the use of genetic sequencing as a reliable tool for monitoring the disease. The findings highlight that even in low-incidence countries, targeted surveillance of specific risk groups is essential to catch transmission chains early and to understand how drug resistance emerges and persists in the community.