The Rise Of Superbugs: How Bacteria Defeat Antibiotics

News stations are constantly warning us about the threats of climate change, hackers, and another season of Fuller House, but what doesn't get enough press is the rise of superbugs. We're not referring to a new species of insect aliens from Starship Troopers, but rather old enemies right here on Earth. Enemies so small that a microscope is required to see them, yet so mighty that just a few of them can spell the end of your existence.

No, that's not what we mean by superbug. We're talking about pathogenic bacteria.

Throughout human history, we've been locked in an ongoing struggle with infectious disease. For much of our existence, pathogenic bacteria have wiped out huge swaths of people and kept our average life expectancy under 50 years. But thanks to the discovery of antibiotics in the early 20th century, most people are no longer dying from skin infections, pneumonia, and tuberculosis.

Alexander Fleming's discovery that a mold (Penicillium notatum) produces a substance (penicillin) capable of killing bacteria revolutionized medicine, giving us the upper hand in the war on infectious disease. However, we are now losing our advantage in this war.

Since the advent of penicillin in the 1940s, antibiotic discovery and research exploded, filling our medicine cabinets with lots of other wicked bacteria-killing drugs with crazy names like the macrolides, tetracyclines, fluoroquinolones, aminoglycosides, and more. By the 1960s, we became so complacent with our pharmacological arsenal that the majority of antibiotic research ground to a halt. Consequently, very few new antibiotics have been developed in the last half-century, leaving us caught with our pants down in the wake of bacteria that have evolved resistance to our current supply of antibiotic drugs.

Speaking of being caught with our pants down, a recent case in point is Neisseria gonorrhoeae, the bacteria that causes gonorrhea. Once easily treated with a shot of penicillin, gonorrhea has quietly evolved resistance to multiple types of antibiotics over the years. Since there is now a danger of gonorrhea being untreatable once again (!), Neisseria gonorrhoeae is considered a superbug by the CDC. Pat Benatar warned us that "Love is a Battlefield"...and now the Huey Lewis request, "I Want a New Drug", takes on an urgent new meaning.

Gonorrhea used to be a very serious infection before the discovery of antibiotics. Today, scientists are sounding the alarm that the bacteria responsible for the infection may no longer be treatable if it continues to evolve resistance and we fail to develop new antibiotics.

There are 26 antibiotic drugs approved for use in the US. Just this week, the news broke that an elderly woman died in Nevada after losing a battle with a stubborn superbug. She succumbed to an infection caused by CRE - carbapenem-resistant enterobacteriaceae (carbapenem is one of our "last resort" antibiotics that is only used when others have failed). In other words, the bacteria that killed her was immune to every single antibiotic we have in our arsenal.

So how do bacteria develop resistance to our medicines? There are at least four different ways. One, bacteria can mutate, or change, the protein that is targeted by the antibiotic. For example, penicillin inhibits a bacterial enzyme called transpeptidase, which is required by the bacteria to build its cell wall properly. Bacteria that acquire a DNA mutation that makes a slightly different version of transpeptidase can become resistant to penicillin (the new version can still build the cell wall, but no longer interacts with penicillin). A related strategy bacteria can use involves increasing the amount of the drug target; in other words, the bacteria could make more transpeptidase - too much for the drug to inhibit effectively.

Two, the bacteria can acquire a gene that makes a protein called penicillinase, which can directly attack the penicillin compound and cut it up. Some bacteria already have this gene and can pass it along to other bacteria that do not have it. Penicillinase is like a bomb diffuser - the bacterial equivalent of Sergeant First Class William James in The Hurt Locker.

Three, bacteria can mutate proteins that are needed for the antibiotic to get into the bacteria cells. Finally, bacteria can also use "efflux" proteins to pump out the antibiotic. These two related strategies effectively keep the antibiotic out of the bacteria and away from its target. A cartoon summary of these mechanisms of antibiotic resistance is shown below.

In summary, bacteria have many ways to combat the drugs we use to kill them. We need to step up our game and fast if we want to stay ahead of the devastating infections bacteria inflict upon us. We need more kryptonite to defeat the superbugs!
 
For more on why bacteria develop resistance to antibiotics, check out this informative video from Everyday Elements.

Contributed by:  Bill Sullivan

Follow Bill on Twitter.

Blair, J., Webber, M., Baylay, A., Ogbolu, D., & Piddock, L. (2014). Molecular mechanisms of antibiotic resistance Nature Reviews Microbiology, 13 (1), 42-51 DOI: 10.1038/nrmicro3380

Attack Of The Germs!

No one likes being sick, especially with the flu. The body aches, the fevers, and the congestion all leave us desperate for ways to end the misery. Indeed, it’s growing increasingly hard to ignore the commercials telling us to stock up on flu-fighting products, like disinfectants and hand sanitizers. But how much do these items really help you avoid becoming the flu’s next victim, and do they have other consequences that we should be aware of?

Let’s first take a look at how many of the popular disinfectants work. Cleaners like Lysol have different types of salts in them that kill germs by disrupting important protein interactions, which causes the pathogen to stop functioning normally. These salts can also work by breaking up the membrane that surrounds bacteria and some viruses, essentially breaking open the pathogen and causing everything inside it to leak out. In both of these cases, the germs stop growing or are killed altogether.

Alcohol-based hand sanitizers work in a similar manner. At concentrations of at least 60%, ethyl alcohol (or ethanol) is effective at killing some viruses, including influenza viruses. Ethanol works by changing the shape of proteins, and therefore interferes with their ability to properly interact with other proteins. Ethanol can also disrupt membranes.

 

Image of Influenza virus from the CDC highlighting proteins on the outer surface that help the virus infect cells, and the viral genome located inside.

While killing off the germs that can make us sick sounds like a good way to stay healthy, the problem with using disinfectants and sanitizers to do this is that these products kill nearly all of the microbes in our environment. While there are many microbes that make us sick, there are also many that we need to help keep us healthy. If we kill those microbes off too, then we may put ourselves at risk for developing other health problems. 

On and within our bodies live millions and millions of good microbes that do things from helping us digest food, to helping keep bad microbes out of our bodies. These good microbes encompass the population known as the microbiome. The microbiome populations shift depending on the location of the body. For example, we have good bacteria that live on our skin, the population of which differs from the population of good bacteria that live in our digestive tracts. There is increasing interest in exploring the functions of the different microbiome populations, and many studies are showing that the microbiome has important roles in keeping us healthy. For example, it is thought that irregularities in the gut microbiome population may have a role in some inflammatory bowel diseases like Crohn’s disease and ulcerative colitis. It is possible that killing off the beneficial microbes in and on our bodies counteracts any good effect from killing off germs.

 

Keeping our good microbes around is only part of the story. According to the CDC, we are currently on the brink of a public health crisis due to the increasing numbers of microbes that are becoming resistant to common antibiotics. Due to our overuse and misuse of antibiotics, we have created strains of bacteria that are no longer susceptible, or able to be killed, by standard treatments. As bacteria populations are constantly exposed to antibiotics, many of those bacteria will be killed because they are sensitive to the antibiotic, but there will be some that are naturally able to withstand the actions of the antibiotic. Eventually, the population of bacteria that was initially a mix of sensitive and resistant will transition to a population of bacteria that is completely resistant, as all of the susceptible bacteria are killed off. What is the impact on us? In 2013, the CDC reported that at least 2 million people in the United States become infected with antibiotic-resistant bacteria, and that at least 23,000 of these people die from their infections.

Perhaps the most well-known case is MRSA, or methicillin-resistant Staphylococcus aureus. Staph bacteria are common and normally cause minor skin infections; however, MRSA has been highlighted in the media several times over recent years due to the outbreaks of invasive infections it has caused due to its resistance to standard antibiotics. MRSA is but one example of the bacterial strains that develop resistance to antibiotics due to constant exposure to them.

As we continue the cycle of overuse and misuse of antibiotics, we eventually will find ourselves at a point where no antibiotics will be effective against bacterial pathogens. Many public health experts suspect that point is near. There is reason to believe that constant use of disinfectants will eventually lead to the development of germs that are resistant to those disinfectants, just as we see happening with bacteria and antibiotics.

So how do we keep ourselves healthy without potentially setting ourselves up for other health problems later? We can start by limiting our use of disinfectants, and go back to simpler, tried-and-true methods of preventing the spread of communicable diseases. Despite the popularity of disinfectants and hand sanitizers, the CDC still maintains that hand-washing is one of the best ways to avoid spreading and catching viral and bacterial infections from others. Wash your hands before you eat, and avoid touching your hands to your eyes and nose.  If you are sick, do your best to sneeze or cough into the crook of your elbow (i.e., do the “Dracula sneeze”) rather than into your hands, and wash your hands frequently to avoid spreading your germs to others.

 

Of course, use soap that does not contain antimicrobial additives, like triclosan, to avoid encouraging the development of strains resistant to this compound. Soap is a potent killer of germs all by itself - it does not need supplemental antibiotics. While some companies are moving away from including triclosan, it is still present in many products, so be sure to check your labels.

Disinfectants have their place; they’re good for cleaning up food preparation areas that have come into contact with raw meat, for example. And, in times when you’re without clean water and soap, hand sanitizer can be a great tool for keeping your hands clean. But as with most things in life, these items should be used with care and arguably in balance with other washing methods in order to avoid creating greater problems down the line.

Contributed by:  Kelly Hallstrom
Visit Kelly’s blog, You Don’t Have To Be A Rocket Scientist
Follow Kelly on Twitter.

 

CDC Threat Report on Drug-Resistant Bacteria:

http://www.cdc.gov/drugresistance/threat-report-2013/

CDC and hand washing:

http://www.cdc.gov/handwashing/

 

Greenblum, S., Turnbaugh, P., & Borenstein, E. (2011). Metagenomic systems biology of the human gut microbiome reveals topological shifts associated with obesity and inflammatory bowel disease Proceedings of the National Academy of Sciences, 109 (2), 594-599 DOI: 10.1073/pnas.1116053109