Image credit: Medical News Today
If for some reason you’re reading part 2 without having read part 1 (which is weird, but live your life), let’s do a quick recap. Antibiotic resistance is gnarly and antibiotic treatment failure is more common than we’d like to think. However, the lab tests used to determine which antibiotic to give to a patient are really good at detecting resistance. So if a doctor knows a bug is resistant to an antibiotic, he/she simply won’t prescribe that antibiotic.
So why is antibiotic treatment failure still so common? A big part of the answer might be antibiotic tolerance. To summarize all of part 1, when bacteria are causing an infection, they’re majorly stressed. Your immune system is trying (and mostly succeeding) to annihilate them and you might be taking an antibiotic that is also trying to kill them. When they’re stressed, they shut down (#relatable) and shutting down means the antibiotics stop working because antibiotics rely on high energy, actively growing bacteria to function.
Microscopy images of Staphylococcus aureus. “Staphylo” comes from the Greek for “cluster (of grapes)” and “coccus” refers to the spherical shape of the cells. Image credits: European Pharmaceutical Review (Left), CDC/ Frank DeLeo (Center), CDC (Right).
All on the same page? Cool. Let’s keep going then. Let’s talk about Staphylococcus aureus, or Staph. Staph is the bacterium responsible for Staph infections. If you haven’t had one, you probably know someone who has. Staph most often causes skin infections (I’ll spare you a photo, you’re welcome), but can also cause more serious infections, like heart infections (endocarditis), pneumonia, bone infections (osteomyelitis), and sepsis (whole organ shutdown that can happen when bacteria get into your blood). Staph also causes toxic shock syndrome, which recently caused the death of a 19 year old woman in Florida.
Although we have antibiotics to treat Staph infections, they often don’t work. But even if they do, these infections can come back up to 70% of the time. For some more bad news, try this on: Staph infections have an average 30% mortality rate and in 2017, Staph infections were responsible for the deaths of 20,000 people in the United States. These really nasty Staph infections were previously considered “nosocomial” or “hospital-acquired.” This means that it was really only people with weakened immune systems (like patients in the ICU) that were getting fatal infections. However, so-called “community-acquired" Staph infections are changing the game.
Staph has now evolved so that otherwise healthy people can get the really bad infections that they used to be (more or less) safe from. Scary, right? Importantly, public health efforts as simple as *washing your hands* can protect you, as well as others, from spreading these dangerous infections.
1 in 10 people to enter a hospital pick up a hospital-acquired infection. Image credit: Healthline
Staph is what we call a facultative intracellular pathogen. Big fancy words that basically mean Staph can live anywhere. Some bacteria are obligate intracellular bacteria, which means they have to live inside of your cells (like the bug that causes Chlamydia), while others are extracellular and like to live outside of your cells (like the bug that causes cholera). Staph likes both, meaning it can grow almost anywhere in your body.
Like the bug that causes chlamydia, this image shows Rickettsia ricketsii, which causes Rocky Mountain Spotted Fever, another example of an “intracellular pathogen.” Intracellular pathogens like to live and grow inside your cells. In the picture, you can see the bacteria (red) inside the human cell (blue)! Image Source: CDC
One of the places Staph likes to hide out is in a type of immune cell called macrophages. Macrophages are responsible for moving around your body and picking up stuff that isn’t supposed to be there, like bacteria. Macrophages, like other immune cells, have an impressive suite of defense strategies they can use to try to kill invaders. Like I mentioned in part 1, one of the ways is to starve the bacteria.
Another way is called respiratory burst. During respiratory burst, your macrophages are launching toxic forms of oxygen at the bacteria. This toxic oxygen can kill about 90% of the Staph inside the macrophage. But unfortunately for us, about 10% survives, and guess what. Our lab found that the toxic oxygen is exactly the type of stress I was referring to that can send Staph into that low-energy lifestyle (aka the persister state).
Throwback to high school biology really quickly. Bacteria, like human cells, have specific cycles involved in generating energy (mitochondria are the powerhouse of the cell!). Now bacteria don’t have mitochondria (in fact they kind of are mitochondria), but they still have to make energy in order to survive. The energy they make is in the form of a molecule called ATP. One of the main ways ATP is made is through the Krebs Cycle (also called the citric acid cycle or the TCA cycle). What we’ve found in Staph is that the toxic oxygen from the macrophages targets Staph’s Krebs cycle, causing it to shut down energy production.
Don’t feel too bad for Staph, though. Staph has other ways of generating energy to stay alive, but by shutting off the Krebs cycle, Staph can enter the persister state.
There are a couple things that can happen next. If you aren’t taking an antibiotic, then Staph will hide out in the macrophage until it eventually starts growing and spreads to other parts of your body (not cool). If you ARE taking an antibiotic, Staph is now in the persister state. And if you remember from part 1, persister state = antibiotics don’t work (also not cool).
Now I know that this all sounds like pretty bad news. You might be thinking that this really sucks and kind of seems like we’re at a dead-end. But fret not friend! As I alluded to in part 1, there are a lot of labs focusing on solving this exact problem (like my own! Second shameless self-plug for the Conlon lab). My research specifically focuses on how exactly that toxic oxygen from the macrophages shuts down the Krebs cycle in Staph. I’m also focusing on how we can change the immune response during a Staph infection so that maybe we can prevent the macrophages from sending Staph into the persister state. So stay tuned, stay healthy…and wash your damn hands.
-Jenna
