Uh Oh! Superbug Alert: Sneaky Resistance Gene to Last-Resort Antibiotics Pops Up in Iran!

Hey everyone! Gather ‘round, because I’ve got some news from the world of superbugs that’s both super interesting and, frankly, a little bit concerning. We’re talking about those heavy-duty antibiotics, the ones doctors save for the really, really tough infections. And guess what? Some pesky bacteria are getting wise to them, and it’s happening in ways we need to keep a close eye on.

The Big Guns: Tigecycline and Eravacycline

So, picture this: you’ve got a nasty infection caused by bacteria that are already resistant to a bunch of common antibiotics. These are often called extensively drug-resistant (XDR) Gram-negative bacteria – quite a mouthful, I know! In these tricky situations, doctors often turn to antibiotics like tigecycline (TGC) and eravacycline (ERV). These are like the superheroes of the antibiotic world, part of a group called third-generation tetracyclines. They were designed to outsmart the usual ways bacteria fight off older tetracycline drugs. Pretty clever, right?

But here’s the rub: bacteria are relentless innovators. Just as we develop new drugs, they’re busy figuring out ways to resist them. And recently, a particularly worrying type of resistance has emerged, carried on plasmids. Plasmids are like tiny, transferable USB sticks of genetic information that bacteria can share amongst themselves. This means resistance can spread like wildfire!

A Nasty New Player: The tet(X) Gene

One of these plasmid-mediated resistance genes is called tet(X). And it’s not just any resistance gene. The tet(X) gene codes for an enzyme – a flavin-dependent monooxygenase, if you want to get technical – that basically chews up and inactivates all tetracyclines. This includes our last-resort heroes, tigecycline and eravacycline, and even newer ones like omadacycline. Yikes! This gene essentially renders a whole class of important antibiotics useless.

The first whispers of mobile tigecycline resistance genes like tet(X3) and tet(X4) came from China in 2019, found in bacteria from both animals and humans. What’s especially troubling is that these tet(X) variants are much more potent than the original Tet(X) enzyme, leading to high-level tigecycline resistance. This is a serious threat to how well tigecycline can work.

The Iran Connection: What Did the Scientists Find?

Now, let’s zoom in on a recent study from Iran. Researchers there were curious about tigecycline-resistant Escherichia coli (you probably know it as E. coli) in livestock, specifically cattle. Why cattle? Well, there’s a growing concern about the link between antibiotic use in food animals and the rise of resistant bacteria that can potentially jump to humans. It’s all part of the “One Health” idea – animal health, human health, and environmental health are all connected.

The scientists collected 395 fecal samples from calves on different farms. They then screened these samples for E. coli that could grow in the presence of tigecycline. Lo and behold, they found some! And when they dug deeper, they looked for the tet(X) gene using PCR (a way to detect specific DNA sequences).

They found five E. coli isolates that were not only resistant to tigecycline (with a high minimum inhibitory concentration, or MIC, of 64 mg/L – meaning it takes a lot of antibiotic to stop them) but also to eravacycline (MIC > 8 mg/L). And all five carried the tet(X) gene. This is the first time this transferable, high-level tigecycline/eravacycline resistance gene, specifically the tet(X4) variant, has been reported in E. coli from Iran. That’s a pretty big deal!

The researchers didn’t stop there. They used a technique called ERIC-PCR to see how related these resistant strains were. It turned out four of them were quite similar, while one was different. So, they picked three representative strains for a super-detailed look using whole genome sequencing (WGS). This is like reading the entire genetic instruction book of the bacteria!

Decoding the Resistance: What WGS Revealed

WGS analysis confirmed that the troublemaker was indeed the tet(X4) variant. The E. coli strains belonged to a couple of different sequence types (STs), specifically ST224 and ST10. Think of STs as different “family lines” of bacteria.

But wait, there’s more! The tet(X4) gene wasn’t traveling alone. These E. coli isolates were carrying a whole cocktail of other resistance genes. We’re talking resistance to:

• Aminoglycosides (like gentamicin)
• Fluoroquinolones (like ciprofloxacin)
• Beta-lactams (including important cephalosporins like ceftriaxone, thanks to genes like blaCTX-M-15 and blaTEM-1B)
• Phenicols (like chloramphenicol, due to genes like floR and cmlA)
• Sulfonamides and trimethoprim

It’s like these bacteria were collecting resistance genes like trading cards! This co-resistance is a huge problem because it means that using one type of antibiotic could inadvertently select for bacteria resistant to many others, including our precious last-resort ones.

The Mobile Threat: Plasmids and Conjugation

Remember those plasmids I mentioned? The WGS data showed that these tet(X4) genes were indeed chilling on plasmids. The specific types of plasmids identified included IncX1, IncQ1, IncI1-I(α), and IncFII/IncFIA/IncFIB. The IncX1 type is particularly noteworthy as it’s known to be a common vehicle for spreading tet(X4) far and wide, across different bacterial species and geographical regions. Some plasmids were even “hybrid” types, which might help them spread to even more kinds of bacteria.

To see just how easily these resistance genes could spread, the scientists performed a conjugation assay. This is basically a controlled experiment to see if the resistant bacteria (donors) can pass their tet(X4)-carrying plasmids to susceptible E. coli (recipients). And guess what? They could! The tet(X4) gene was successfully transferred, making the previously susceptible recipient bacteria highly resistant to tigecycline and eravacycline. The transfer frequencies were around 10^-9 to 10^-10, which might sound small, but in a large population of bacteria, it’s definitely enough to be a concern.

What’s more, the resistance was stable. The researchers grew these newly resistant bacteria (and the original donors) for 10 days in media without any antibiotics. Even without the pressure of the antibiotic, most of the bacteria held onto their tet(X4)-carrying plasmids. In some cases, the retention rate was over 96%! This means the resistance isn’t just a fleeting thing; it can persist.

Why is Tigecycline Resistance Spreading in Animals?

Here’s a curious bit: tigecycline isn’t even approved for use in veterinary medicine. So why are we seeing tigecycline resistance genes popping up in animals? The study suggests that the extensive use of older tetracyclines and possibly phenicols (like chloramphenicol) in livestock could be creating the selective pressure. It’s like the bacteria are being trained to resist these older drugs, and in the process, they accidentally pick up or maintain resistance to the newer ones like tigecycline.

In the farms where these tet(X4)-bearing strains were found, antibiotics like oxytetracycline (an older tetracycline), enrofloxacin (a quinolone), sulfonamides, and ceftiofur (a cephalosporin) were commonly used. This supports the idea that use of other antibiotics can co-select for tigecycline resistance. It’s a complex web of resistance development.

The Bigger Picture: A Public Health Concern

So, what does all this mean? The emergence of transferable, high-level tigecycline and eravacycline resistance, like that conferred by tet(X4), is a significant public health threat. E. coli is a common bacterium, and while many strains are harmless, some can cause serious infections. If these resistant strains, or the plasmids they carry, make their way from animals to humans – perhaps through the food chain or environmental contamination – we could face infections that are incredibly difficult, or even impossible, to treat.

The recovery rate of tet(X4)-positive E. coli in this Iranian study (1.26%) was actually higher than in some other studies from China, though lower than rates found in retail pork or wastewater in other regions. This highlights that the prevalence can vary, but the presence itself is alarming.

The fact that tet(X4) has been found in diverse E. coli STs, including common ones like ST10 (which was found in this study), suggests it’s pretty good at spreading. And as I mentioned, IncX1 plasmids are known for their broad host range and efficient transfer, making them excellent vehicles for disseminating tet(X4) globally.

What’s Next? The Need for Vigilance

This study is a crucial wake-up call for Iran and, indeed, the global community. While no human cases of tet(X4)-positive bacteria have been reported from Iran yet, the potential is there. These animal-originated strains could jump to humans or share their resistance plasmids with human pathogens.

So, what’s the game plan?

• Enhanced surveillance: We urgently need to monitor for tet(X4)-harboring pathogens in clinical settings, in animals, and in the farming environment. Knowing where these superbugs are is the first step to controlling them.
• Antibiotic stewardship: It’s critical to regulate and reduce the use of tetracyclines (and potentially phenicols) in food animals. This can help lessen the selective pressure that drives the emergence and spread of resistance.
• One Health approach: We need to tackle antibiotic resistance from all angles – human, animal, and environmental. It’s all interconnected.

Discoveries like this are a stark reminder that the fight against antibiotic resistance is ongoing and requires constant vigilance. By understanding how these resistance genes emerge and spread, we can develop better strategies to protect these invaluable medicines for future generations. It’s a bit of a detective story, and every clue, like the findings from this Iranian study, helps us piece together the bigger picture. Let’s hope we can act on these clues before it’s too late!

Source: Springer Nature