If you could poke holes in a bacterium's membrane, would it be like a water balloon, leaking all over the place until it died? In this lesson, learn how short proteins called peptides can specifically damage microbial plasma membranes.
Microbes - they are tiny, simple creatures that don't even have brains, but they can still be formidable enemies when they infect us! These little boogers have ingenious ways to take control of our bodies and use them as breeding grounds. When an infection happens, we have to weaken them in any way possible!
What better way to weaken a cell than to destroy its membrane? A membrane is what separates a cell from the rest of the outside world and keeps all of a microorganism's goodies inside! Today, we'll talk about how antibiotics and even our own natural proteins can kill microbes by damaging their plasma membranes.
General Mechanism of Action
The molecules we are going to talk about in this lesson are peptides, meaning they are short proteins that are approximately 12-50 amino acids long. There is still a lot of research being done on these peptides to find out exactly how they work, but for now, we know that their general mechanism is to interact with membranes and disrupt them. Some of the peptides may form pores or holes in the membrane, others may change the membrane structure by poking into it in many places, and there may even be other mechanisms that scientists haven't even imagined yet. But, the bottom line is these peptides damage membranes and make them more permeable.
When a microbe's membrane is too permeable, it will die. One reason is that it can lose important metabolites and ions, and molecules from the environment that the microbe would rather keep out can come right in. This would be kind of like if all the doors and windows of your house got broken or ripped out. A lot of your possessions might suspiciously go missing, and people, animals, and weather conditions would have free access into your home.
In cells, other crucial everyday processes can stop because of membrane damage. One of these processes is cellular respiration, which is how the cell makes its main energy source, ATP. Without ATP, a microbe won't be able to get anything done at all. This would be like adding insult to injury: on top of the problems you're dealing with in your windowless and doorless house, the electricity stops working. Not fun.
Let's look at a few examples of peptide antibiotics, which are peptide molecules that are used as antibiotics. One important example is Polymyxin B, which damages the plasma membranes of Gram-negative bacteria. Polymyxin B used to be an important antibiotic for treating pseudomonas infections but is now mainly found in antibiotic creams you might use at home for minor wounds.
Daptomycin is a newer peptide antibiotic. Instead of just being a peptide antibiotic, it is a lipopeptide antibiotic, meaning that it is a peptide with a lipid chain attached to it. This allows it to very effectively attack the Gram-positive bacterial membrane. Like other peptide antibiotics, daptomycin changes the plasma membrane structure, forming holes that make the membrane more permeable. It is used to treat infections with multidrug-resistant pathogens like methicillin-resistant Staphylococcus aureus, MRSA for short.
Antimicrobial Peptides in Immunity
In addition to the peptides that are used as antibiotics, many organisms naturally make and use antimicrobial peptides (AMPs) as part of their normal immune systems. Antimicrobial peptides have been found in various different organisms, such as amphibians, birds, insects, mammals, and even plants. They may be a part of an evolutionarily ancient system for immune defense.
Let's look at a few examples. The magainins are antimicrobial peptides that are found in the skin glands of amphibians, such as frogs. Our own cells have antimicrobial peptides, too. Neutrophils, an important type of white blood cell in our innate immune system, produce alpha-defensins, and another antimicrobial peptide called dermcidin is present in our sweat. All of these antimicrobial peptides can disrupt the membranes of bacteria and sometimes even fungi and other eukaryotic pathogens.
A really cool fact about antimicrobial peptides is that, even though they've been around for a very long time through evolution, very little resistance has developed. Perhaps it is too difficult for microbes to evolve new types of membranes that would not be affected by these peptides. Since antibiotic resistance is a major problem in medicine today, scientists are continuing to research antimicrobial peptides in the hopes of creating new antibiotics with similar strategies.
But hang on a minute; we've been missing something really important here. All cells have plasma membranes, which are all composed in pretty much the same way. Remember that plasma membranes are lipid bilayers formed of many phospholipid molecules arranged so that their hydrophilic, water-loving head groups are on the outsides and the hydrophobic, water-fearing tails are all hanging out together in the middle of the membrane.
So, how on Earth could these membrane-disrupting peptides be selectively toxic if our cell membranes are so similar to microbial cell membranes? Again, scientists don't know for sure how this works, but one important idea is that the surface charge of microbes could be a major factor. Our cell membranes tend to have a neutral charge on the outside, but bacterial membranes are more likely to have negatively charged phospholipids on the outside. In addition, bacteria have other negatively charged molecules on their surfaces as well, like lipopolysaccharide (LPS) in Gram-negative bacteria and teichoic acid in Gram-positive bacteria.
The bottom line is bacterial surfaces tend to be negatively charged. How convenient, then, that antimicrobial peptides tend to have a positive charge. The electrostatic attraction brings the positively charged peptide to the negatively charged bacterial surface, where it can poke into the bacterial membrane or otherwise damage it. If antimicrobial peptides were made of Velcro and bacterial surfaces were coated in the other type of Velcro, they could stick together. Our cells, on the other hand, don't have any Velcro on them at all, so the antimicrobial peptides won't attach to them very well.
That said, nothing is perfect in biology. Some antimicrobial peptides could still accidentally damage our cells' membranes - for example, if they were present in particularly high concentrations. Like dealing with any potentially dangerous substance, our body has ways to handle the peptides safely. At home, if you had a really hot cookie sheet that just came out of the oven, you'd take some precautions to avoid accidents. You'd use oven mitts to touch it, you'd put it down on the stove instead of somewhere that could be damaged by the heat, and you wouldn't let any kids get near it.
Likewise, our bodies are careful about the use of antimicrobial peptides. Immune cells, like neutrophils, tend to keep their antimicrobial peptides, like defensins, inside of the cell in the compartment where the invading microbes are. They don't just dump the defensins anywhere where they could come into contact with host cell membranes. Another place where antimicrobial peptides are located is the outside of the skin. You may know that the cells on the outside of our skin are already dead anyway, so this is a perfect place for antimicrobial peptides to kill microbes without harming our own cells.
Today, we've learned about short proteins called peptides that kill microbes by damaging their plasma membranes. Peptide antibiotics such as Polymyxin B and the lipopeptide daptomycin are used as antibiotics, and organisms such as amphibians, mammals, insects, birds and plants can make antimicrobial peptides naturally on their own, too! We heard that frogs release magainins on their skin and that our own bodies produce alpha defensins in some of our immune cells and dermcidin in our sweat.
What do all of these peptides do? We learned that they interact with membranes and disrupt them. They can form pores or holes in membranes or change the membrane structure in other ways. The peptides all make the plasma membrane more permeable, which kills the cell.
Finally, we learned that antimicrobial peptides are usually positively charged, whereas bacterial surfaces are usually negatively charged. This helps with selective toxicity, as the peptides are more attracted to bacterial surfaces than to our own cells' neutral membranes. Also, our bodies take precautions to avoid damaging our own cells with these peptides. They keep them sequestered inside of immune cells or put them on parts of the body like the skin, where there aren't many live cells around that could be harmed.
After finishing this lesson, you could have the ability to:
- Outline the methods by which antimicrobial peptides can destroy or disrupt cell membranes
- Highlight examples of peptide antibiotics and natural antimicrobial peptides
- Recognize the importance of antimicrobial peptides being positively charged and bacterial surfaces being negatively charged
- List some ways in which the human body protects against damage to our own cells from antimicrobial peptides