How Does A Deadly Food Poisoning Bacteria Share Antibiotic Resistance Genes?
Originally published on Forbes
Bacteria are able to develop resistance to antibiotics in a number of ways. They can exploit existing defense systems to react to new antibiotics, but they also regularly take advantage of genetic mutations.
These mutations arise more or less at random, but if a bacterium gets lucky, it will experience a mutation that will enable it to evade an antibiotic attack. For example, perhaps the mutation causes a tweak in a molecule that is usually targeted by an antibiotic; consequently, the target molecule still works well enough, but it has changed just enough that now the antibiotic can no longer disrupt its function.
At the outset, it’s a numbers game. All it takes is for one bacterium in a vast population to develop resistance in this way, and it will survive to produce offspring. Of course, if antibiotic resistance could only take hold through random luck and reproduction, we would not be in the fix we are currently in.
Instead, the major contributor to the rapid rise of antibiotic resistance is the fact that some strains of bacteria are very good at horizontal gene transfer: they can share their resistance genes with their neighbors.
Exactly how bacteria are able to do this isn’t fully understood. Bit by bit though, scientists are building a picture of how the transfer process works and a number of genes have been identified as contributors. For example, some genes are known to be involved in forming the molecular channel that enables DNA to pass directly between the donor and the recipient.
Of course, making the connection is only one part of it. Not surprisingly, evidence suggests that the transfer process must be tightly controlled — in other words, the bacteria aren’t sharing just any DNA with their neighbors.
Now, Daouda Traore and his colleagues at Monash University have gained some intriguing new insight into why a dangerous bacterium called Clostridium perfringens is so good at sharing its genetic information. They have discovered that a gene called tcpK plays an important role in earmarking the tetracycline resistance DNA for transfer to other bacteria.
The potentially lethal C. perfringens is a leading cause of food poisoning worldwide and is responsible for more than a million cases of food poisoning each year in the US alone.
C. perfringens is found in soil, food, and sewage, and has also been found in the gut microbiomes of humans and animals. In fact, identification of C. perfringens in the mummified gut of the ‘Tyrolean Iceman’ found in the Ötztal Alps in 1991 suggests this species of bacteria has been associated with the human microbiome for at least 5000 years.
C. perfringens was first identified in the late 1800s and by the First World War, it was known to be responsible for gas gangrene. The advent of antibiotics revolutionized its treatment, but in 1968 something changed.
That year, tetracycline resistance in C. perfringens was first reported. After that, other antibiotics were recommended for the treatment of Clostridial infections but by 1977, multidrug-resistant strains were beginning to appear.
According to the new research, it seems that the tcpK gene plays an important role in sharing DNA associated with tetracycline resistance.
First, they found tcpK in a genetic region known to be important for transferring tetracycline resistance DNA from one bacterium to another. They hypothesized that it was somehow involved in this process, but they didn’t have much else to go on.
"We couldn't find any clues as to TcpK function anywhere," says Traore.
When they inactivated the gene, though, the bacteria were no longer very good at sharing the DNA.
Daouda’s colleague Vicki Adams, explains, "It's only found in C. perfringens and related disease causing bacteria, but is critical for the bacteria to spread antibiotic resistance.”
Knowing that tcpK is essential to DNA transfer was one thing, but it didn’t explain what it was doing. If you take the battery out of your car, you won’t be able to start your car. That tells you it’s essential, but it doesn’t really tell you how the battery works or why your car needs one.
The tcpK gene makes a protein called TcpK, and to determine how it works, the researchers figured out what it looks like at the molecular level by using a method called X-ray crystallography, in which a crystal made of the protein is bombarded with high-energy X-rays, and the patterns they make provide information about the 3D shape of the protein.
"Our structural analysis revealed that the molecule resembles a universal DNA binding module called a winged-Helix-turn-Helix,” says Traore.
This recognizable structure led to the discovery that TcpK is able to bind to a critical piece of DNA near the antibiotic resistance gene, and in doing so, helps signal to other molecular machinery that this genetic information is ready to share.
“This was the key breakthrough that allowed us to discover that TcpK works by marking the DNA for transfer to another bacterium,” he says.
The findings help fill in an important part of the picture of how tetracycline resistance arose in C. perfringens.
Sharing of genetic information between bacteria is a complex process, but now that it’s known that this particular DNA binding molecule plays a critical role in sharing tetracycline resistance, researchers can see if a similar factors contribute to other forms of antibiotic resistance, too.
Ultimately, a better understanding of how deadly bacteria share resistance genes could reveal ways to disrupt those processes, and perhaps lead to the development of interventions that control the spread of antibiotic resistance.