90 Years Ago, A Contaminated Petri Dish Changed The World

Scientists throw away contaminated petri dishes every day. There is probably a frustrated researcher chucking her petri dishes into the bin right now as you read these words, cursing at the contaminant that ruined her experiment. 

In those petri dishes are soft beds of agar that bacteria feast upon. Hundreds of bacterial colonies grow on the agar, each one containing millions of bacterial cells. But fungal spores lurk in the air, and if one of them happens to land on the agar, it may grow better than the bacteria. When a mold appears in a researcher’s bacterial dish, it is not a good thing.

Alexander Fleming stares menacingly at a plate of bacteria.

Unless you were keeping your eyes peeled for a substance that can kill bacteria. In the 1920’s, a scientist named Alexander Fleming at St. Mary’s Hospital in London was doing just that. Fleming was growing colonies of Staphylococcus aureus bacteria on his petri dish plates. Staphylococcus aureus is commonly found on the skin, where it normally lives in peace. But it can turn into a deadly troublemaker if it finds its way into the bloodstream. One of Fleming’s first discoveries was that snot could kill the bacteria. He soon isolated the murderous enzyme (lysozyme), but it proved to be a rather weak assassin with no viable therapeutic potential. Besides, it would have been a marketing nightmare...what would you call it? Snoticide? Boogie bombs?

One fateful autumn day in 1928, Fleming arrived at his laboratory to a pile of petri dishes that needed cleaning. While sorting through them, he noticed a mold growing on one of his culture dishes of Staphylococcus aureus. Fleming had undoubtedly seen a contaminated dish of bacteria before, but something more caught his eye that day. It turned out to be the discovery of a lifetime – one that has saved an incalculable number of lives.

As Louis Pasteur said, “Chance favors only the prepared mind.” Fleming’s mind was prepared, and he was always on the lookout for things that could kill bacteria. On that contaminated plate of Staphylococcus aureus, he astutely noted that bacterial colonies grew better if they were farther away from the mold. In fact, no colonies could grow next to the mold. He figured that the mold was producing a substance that was actively killing bacteria that dared to come near it. The miserly mold would want to do this so it could have all the nutrients to itself. Fleming named this mystery bacteria-slaying substance penicillin, since the species of contaminating mold was called Penicillium.

The famous plate showing bacterial colonies being
killed by the mold, Penicillium.

Fleming published this extraordinary finding in the British Journal of Experimental Pathology in 1929 and the world…paid absolutely no attention to it at all. Pathogenic bacteria continued to lead tens of millions of people to early graves through the 1930’s. Fleming was no chemist, so he was not in position to isolate the active ingredient in the mold that was killing the bacteria. He needed help. But try as he might, Fleming couldn’t get other scientists interested in the promise of mold as a remedy for bacterial infections.

In hindsight, that seems crazy. But there were practical issues that dampened enthusiasm for his idea. At the time, fungi were very difficult to grow in bulk, and the strain of Penicillium Fleming promoted produced very little penicillin. Fleming’s follow-up studies also suggested that penicillin would not work well in the clinic. Because it was so rare, he was forced to use low doses in his attempts to treat ill patients. He also applied the “mold juice” topically on the skin instead of injecting it into the bloodstream, which would have been far more effective. These poorly designed experiments led many to the false conclusion that penicillin was an impotent bacterial assassin. You can imagine the skeptics dismissing his work: “First snot, now mold juice? C’mon, Fleming.” Consequently, Fleming’s discovery laid dormant for over a decade.

In 1939, while leafing through back issues of the British Journal of Experimental Pathology, a chemist at Oxford named Howard Florey decided to revisit Fleming’s ignored penicillin paper. Together with Ernst Boris Chain, this dynamic duo produced a highly purified mold extract and injected it into mice with sepsis. They soon published the striking result that their Penicillium extracts cured the mice of this deadly bacterial infection.

Imagine Fleming’s response when he woke up one day to read this report! Fleming was thrilled that someone was making use of his old work and immediately called Florey to arrange a visit to their laboratory. Chain was surprised to hear that he would get to meet Fleming, as he was under the impression that Fleming had passed away. The trio won the 1945 Nobel Prize in Physiology or Medicine and inspired many microbiologists to search for more bacteria-killing microbes out in the wild. Before long, our medicine cabinet was filled with additional antibiotics like erythromycin, tetracycline, streptomycin, and many more. These wonder drugs were being produced naturally by microbes found in the dirt, on rotting foods, and even in the throat of a chicken. Scientists left no stone unturned in their hunt for weapons of microbial destruction.

It took ten years before a pair of scientists took Fleming's paper on penicillin seriously. It makes one wonder: How many other medical treasures are buried in obscure scientific journals?

The story would have a happy ending were it not for two things. In an interview after his Nobel acceptance speech, Fleming gave a very prescient warning about the reckless overuse of antibiotics: "The thoughtless person playing with penicillin treatment is morally responsible for the death of the man who succumbs to infection with the penicillin-resistant organism." Unfortunately, we failed to heed Fleming’s premonition and now face an imminent threat of “superbugs,” bacterial strains that have evolved resistance to these precious medicines. Poor Fleming...ignored twice, but later proven correct on both accounts. Second, virtually no one is in the business of antibiotic discovery anymore because it does not generate high profits like medicines for chronic conditions, which patients must take every day for the rest of their lives. Considered together, Fleming’s near-century old discovery may soon be ineffective and we will return to the “pre-antibiotic” era when a simple scratch from a rosebush could mean death. We need more “prepared minds” in research and in business to keep the antibiotic pipeline strong.

Contributed by: Bill Sullivan

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Bill is writing a book! PLEASED TO MEET ME: The Hidden Forces Shaping Who We Are arrives in August 2019 from National Geographic Books.

If Parasites Had Dating Profiles

Once upon a time, before the Internet, people actually had to venture outside to find a significant other. Popular places to find a potential mate included bars, dance clubs, dog parks, cafes, parties, and the gym. You’d have to work up the courage, and perhaps a cringe-worthy pick-up line, to ask another person out on a date. After an overpriced dinner and movie, you’d have to engage in lengthy conversation under a starry sky to learn about them.

But who has time for all that?! These days, you can simply screen dozens of candidates by reading their dating profiles on matchmaking web sites or apps like Tinder. This modern form of mate selection is unique to humans; imagine if other creatures in the natural world, like parasites, had to write dating profiles…

Toxoplasma gondii

Hanging with my BFFs in a tissue cyst.

We call ourselves "The Brady Bunch"!

Photo by David Ferguson (via EurekAlert)

Do you love cats? So do I! They’re my favorite animal, although I can weasel my way into any vertebrate animal that I want to, including weasels. That’s one of the reasons why I’m called “the most successful parasite on Earth.” I’m the clever parasite that has learned to manipulate the brains of rodents so that they become fearless morons around felines. Normally, mice and rats scurry away from the scent of a cat, but not when I’m in their head!

What turns me on? Long, romantic walks through the hollows of a cat’s innards. I like to groove under the moist sheets of their intestinal epithelium to the musical stylings of Cat Stevens. If we have kids, I promise to be a good parent and read Calvin and Hobbes to them all night long. I’ll be sure to kiss them goodbye before sending them out into the world to contaminate litter boxes, sandboxes, gardens, yards, and streams. Before long, our progeny will be inhaled or ingested by unsuspecting animals.

When I get into something that is not a cat, I get bored rather quickly and go to sleep. You can call me bradyzoite when I’m napping. Life in my intermediate host isn’t all that bad. I can pick pretty much whatever cell type I want and make it my room. The neurons in the brain are ideal because the pesky immune system tends to leave that organ alone, so I get plenty of peace and quiet. I just chill and wait for that animal to get eaten, hopefully by a cat so I can get my groove on again! What if another type of animal eats me instead? No biggie. I’m a patient parasite and will simply wait it out in another intermediate host.

Like I said before, if I landed in a rodent I know how to scramble their tiny brains to increase their chances of getting eaten by a hairball-coughing feline. The human brain is a tad more complex and taking me a little longer to figure out. While knocking around in a human head, I might have increased the risk of some people to develop schizophrenia or rage disorder. But ultimately, I’m trying to rewire the human brain so they leap into lion cages at the zoo.

In my spare time, I love to devour books instead of organ meat. My favorite books include Cat’s Cradle, The Pink Panther, The White Tiger, and of course The Cat in the Hat. I’m also writing my own book. It’s called If You Give A Mouse Toxoplasma…

Schistosoma mansoni

Come swim with Schisto!

Photo: http://schaechter.asmblog.org/.a/

6a00d8341c5e1453ef014e875d2f3e970d-popup

Escargot, anyone? My name is Schistosoma, but you can call me Schisto. I live in parts of South America and the Caribbean, Africa, and the Middle East. I hope you don’t think I’m being too fresh, but I’d love to start our date by skinny dipping in my favorite freshwater lake. After we’re done frolicking in the water, we’ll sneak into some snails and develop into cercariae. What? You’ve never been a cercariae before? Have no fear, my darling, I will teach you how to become one. Once we’re cercariae, we’ll break out of the snail and search for the definitive stop on our romantic adventure: an unsuspecting human swimming in our waters.

The cool thing about becoming cercariae is that we’ll look like a mermaid. We’ll gain a gorgeous forked tail that will help us swim around and find a suitable human to invade. I like to hum the theme to Jaws as I make my approach to the human creature! Do you know how many people are attacked by sharks each year? Only 75. I've infected well over 200 million people, but sharks get the scary theme song...go figure!

I think you’ll be surprised how easy it is to burrow into a human's skin – I prefer to enter through a hair follicle. They don’t feel a thing. Once we get inside a human, we can ditch our tails and I’ll give you a grand tour. After a few days gallivanting through the skin, we’ll hang out in the lungs, go through the heart, and then enjoy a bloodmeal as we take a ride in the circulatory system to the liver. This is the stop I find most arousing, and I’ll ask you to pair-bond with me. If you accept, we’ll celebrate by making our way to the veins draining the colon.

Why the veins of the colon? I’m glad you asked, my pet! You see, the colon is where the human stores his waste until he can’t hold it in any longer. We can easily send our eggs into his colon, giving our kids a free ride back out into the water so they can find snails of their own one day. It’s a strategy not unlike the one used by Han Solo in The Empire Strikes Back when he evaded the Star Destroyer by making it appear his ship was just a part of the Imperial garbage.

I think you’ll find that the chemistry between us is no fluke, but rather truly meant to be.

Trypanosoma cruzi

Come cruzi with me! I'm the cute wavy purple things!

Photo: Wikipedia Commons

What could be more romantic than a date that involves a “kissing” bug? That is where our enchanting evening shall begin. From inside the so-called kissing bug, we will watch it latch onto human flesh and suck its blood – cool, huh? After the kissing bug has its fill, it gets the urge to go to the bathroom, using the tiny wound it made as a toilet. That will be our cue to exit: out of the kissing bug, into the human – right through that convenient little hole the bug made in its flesh.

Once under the human’s skin, we’ll transform from trypomastigotes into amastigotes while inside the host’s cells. I hope you don’t think I’m being too prudish, but I’m really not all that into sex. I’d prefer that we multiply on our own, but how about this…we can watch each other divide!

After we make clones of ourselves, there will be too many for the host cell to hold. I just love it when a host cell pops, don’t you? As trypomastigotes again, we’ll be free floating in the blood, where we will hitch a ride when the next hungry bug comes along to “kiss” our human host.

I just hope the kids we leave behind don’t cause trouble. Most of the time when I go through a human, my kids get all rowdy and start having a bunch of kids of their own. The extensive damage they leave in their wake can cause serious problems for the human host, which they call Chagas disease.

While waiting for a kissing bug to pick me up, I enjoy listening to music. Some of my favorite songs include Kiss Me Deadly, Love Bites, and Blow Me (One Last Kiss).

Plasmodium falciparum

I'm a little camera shy, but I like these plushies of me

as they show my softer side!

Photo: Giant Microbes

If you have a fetish for vampires or other blood-sucking creatures, I am the parasite for you! My name is Plasmodium, but most people know me as malaria, which means “bad air.” I hasten to clarify: I do not suffer from flatulence or rancid breath. Before people realized I was a parasite, they attributed the cause of malaria to breathing in “bad air.”

Two of my favorite things in life are blood and sex. I use humans for blood and Anopheles mosquitoes for sex. You might not think that there is enough room in the gut of a mosquito to have a lot of great sex, but give me a chance and I’ll show you that size isn’t everything. After the love making, we’ll take a lovely stroll up to the mosquito’s salivary glands and take a little nap before dinner. While we’re in the salivary glands, you can call me sporozoite.

The mosquito will be our limo to a fine human restaurant where the blood flows like wine. We will get our wake-up call when the mosquito bites a person; then hang tight while we take an exhilarating slide down her proboscis and into a red river. After a quick pit stop in the liver to transform into merozoites and put on our bibs, we’ll jump back into the red river and take our pick at which blood cell we’d like to dine at first. All the hemoglobin you can eat! We will be the envy of Count Dracula!

In humans, red blood cells carry oxygen around the body, so as we destroy them, our human host will soon feel woozy, suffering from anemia, chills, and fever. But have no fear, as I’ll send out an SOS that changes our victim’s scent to be more attractive to mosquitoes. Before you know it, we’ll be pulled up into a fresh mosquito for some more amore.

I’m also a huge movie buff. My favorite movies are The Mosquito Coast, There Will Be Blood, Jungle Fever, and Red River.

Contributed by: Bill Sullivan

Follow Bill on Twitter.

Could Parasites Be Causing Prostate Cancer?

Long ago in the mid-1600s, a fellow named Antonie van Leeuwenhoek started making lenses…as a hobby (remember, Facebook and Netflix were not invented yet). He was so adept at grinding glass that his lenses were able to magnify objects about 270 times their normal size. Leeuwenhoek soon discovered a whole new universe right here on earth, a universe of creatures so tiny that only his microscope could reveal them. He called them "animalcules."

With his powerful microscope, Leeuwenhoek became the first person to see amoebae, bacteria, and blood cells. For these revolutionary discoveries, he is considered “the father of microbiology.”

But after looking at endless water samples, the ever-curious Leeuwenhoek wondered what bodily fluids looked like under his microscope. While Leeuwenhoek examined blood, sweat, and tears (and a lot of dental plaque), a medical student in 1677 named Johan Ham told Leeuwenhoek that he spotted animalcules swimming in the semen he collected from a gonorrhea patient.

Believing these animalcules might be a result of disease, Leeuwenhoek procured a clean semen sample from his own stock - obtained fresh after proper lovemaking with his wife, he insisted. Leeuwenhoek confirmed Ham's finding and went on to discover the same tiny eel-like critters teeming in the semen from many other species. This is how we came to make the “seminal” discovery of sperm cells.

Other people in Leeuwenhoek’s day mistook these microscopic beasties squiggling around in the semen to be "merely" parasites, referring to them as “seminal Worms.” In fact, we didn’t realize that these “semen parasites” played a key role in fertilization until the 1870s when Oscar Hertwig spotted the fusing of nuclei from sperm and egg after contact…in sea urchins of all places.

We didn’t figure out where babies come from until fairly recently – 1870. White studying sea urchins, Oscar Hertwig noticed that the nucleus in the sperm fuses with the nucleus in the egg (the nucleus is the cellular organelle housing DNA).

While the mystery of sperm has been solved, we have indeed discovered a variety of pathogens that can inhabit our nether regions. Trichomoniasis, scrotal filariasis, and Chlamydia are just some of the unpleasant conditions caused by these most intimate of uninvited guests. An unsettling new study led by graduate student Darrelle Colinot at the Indiana University School of Medicine may have found yet another.

In experiments performed in mice, researchers found that the common single-celled parasite called Toxoplasma gondii disseminates to the prostate within two weeks after infection. And there it remains in the form of latent tissue cysts for at least sixty days, but probably for the rest of the host’s life. The presence of these parasitic cysts led to chronic inflammation in the prostate, which is a precursor to benign prostatic hyperplasia (BPH), the reason why older men have to get up multiple times to pee at night. Chronic inflammation in the prostate is also connected to prostate cancer, which afflicts more than 200,000 men in the US each year.

Parasites in prostates. The control panel shows cells from an uninfected mouse prostate (the nuclei are stained blue). The other panel shows the presence of a Toxoplasma tissue cyst (green) in the prostate 14 days post-infection (14 D.P.I.).

If Toxoplasma is also found to trigger chronic inflammation in human prostate, the finding takes on added significance given the prevalence of the parasite in the human population. According to the CDC, up to 22% of Americans are infected with the parasite, which is transmitted through oocysts that are excreted into the environment by infected cats or through tissue cysts present in game and livestock. 

Women are commonly advised to avoid gardening, changing the litterbox, and consuming undercooked meat while pregnant so the parasite doesn’t transmit to the fetus. Men may need to heed these warnings as well to avoid a prostate full of parasites, but a lot of critical work still needs to be done before we can ascertain whether this discovery has relevance to prostate issues in humans. Regardless, our study introduces Toxoplasma-infected mice as a powerful new model for the study of prostatic inflammation.

Prostate cancer is believed to arise from a constellation of events that can involve a person’s genes and environmental exposures. Infectious agents and carcinogens have previously been proposed as agents that can injure the prostate and lead to the development of chronic inflammation. Numerous types of bacteria and viruses have been shown to infect the prostate and cause an inflammatory response; this new study in mice suggests that the parasite Toxoplasma might be added to this list.

Contributed by:  Bill Sullivan

Note:  Bill Sullivan is a co-author on the study highlighted in this article.

Follow Bill on Twitter.

Reference:

Colinot, D., Garbuz, T., Bosland, M., Wang, L., Rice, S., Sullivan, W., Arrizabalaga, G., & Jerde, T. (2017). The common parasite induces prostatic inflammation and microglandular hyperplasia in a mouse model The Prostate DOI: 10.1002/pros.23362

Unsung Heroes In Our Battle Against Infectious Disease

Humanity has always been at war with infectious agents, but it wasn’t until 1860 when Louis Pasteur famously theorized that microbes (first observed by Antony van Leeuwenhoek in the 1600s) cause disease. It took another 70 years before Alexander Fleming noticed that Penicillium mold produced a substance that killed bacteria. While most people are familiar with these luminaries in the field, have you heard of Francesco Redi, Ignaz Semmelweis, Theobald Smith, Mary Hunt, and a cow named Blossom? In this presentation, we celebrate some of the “unsung heroes” whose victories are often neglected from the infectious disease saga.

In the talk below, Dr. Bill Sullivan, a professor at the Indiana University School of Medicine, takes us on a fascinating tour through medical history, answering these questions and more:

How did we figure out that microscopic creatures can make us sick?

Why were milkmaids considered to be so beautiful and what does that have to do with vaccination?

How were starfish important to the discovery of the immune system?

What do you mean penicillin wasn't the first antibiotic?

Watch the talk "Unsung Heroes In Our Battle Against Infectious Disease" by Bill Sullivan here.

Bugs To Drugs: Can Probiotics Treat Depression?

Depression is a debilitating mental illness that affects up to 15 million Americans in the US alone, yet we are far from understanding the root cause. Multiple genes have been associated with depression, but whether these genes produce symptoms depends on the individual’s environment. New research is showing that one of the biggest environmental factors impinging on mental health comes from within.

Our body is home to trillions of microscopic creatures, mostly bacteria, which are collectively referred to as our microbiota. As unsettling as that may sound, these microbes are not necessarily the kind we want to evict from our body. The bacteria dwelling within our gut serve many important functions; for example, they help digestion, produce vitamins, and keep other types of microbes that cause disease at bay.

Our microbial inhabitants bring countless additional genes into our body called the “microbiome.” These microbial genes can be considered an extension of our own DNA – a so-called “second genome.” In other words, your body is not only influenced by the genes in your DNA, but it can also be affected by genes carried by your microbiota. These microbial genes not only affect physical health, but may also alter your mood and personality.

It is convenient to refer to species of our microbiota as "good" or "bad", but in reality they are neither. There are bacteria that can cause serious disease, like C-diff, but usually only after the microbiota has been disrupted (e.g. after prolonged antibiotic treatment). Likewise, "good" bacteria like E. coli can cause life-threatening disease under the right circumstances.  

Our microbiota help produce surprising amounts of neurotransmitters – chemicals that function in brain signaling. When laboratories produce “germ-free” mice by raising them in sterile environments, the mice exhibit strange neurological issues. Lacking their gut microbiota, germ-free mice do not respond to stress properly. These studies have given rise to the concept of the “gut-brain” axis, a conduit of biochemical communication between these organ systems. Such an axis exists in people too, as researchers have noted a strong correlation between intestinal problems and mental illness. For example, anxiety and depressive disorders are associated with both irritable bowel syndrome and ulcerative colitis.

A study by Ioana A. Marin and colleagues at the University of Virginia, published on March 7, 2017 in Scientific Reports, provides new evidence that intestinal bacteria influence mental disorders such as depression. In this experiment, mice were subjected to unpredictable chronic mild stress (UCMS), which involves strobe lights, irritating noise, cage tilting, and crowded conditions. Kind of like being shoved into noxious nightclubs against your will at random times throughout the day.

Unlike Disco Mickey, laboratory mice become stressed out when subjected to stimuli that resemble your average nightclub.

Over time, mice subjected to UCMS begin to show symptoms that resemble depression in humans. The researchers look for “despair behavior,” which can be detected in a number of ways. In this study, the mice were placed in a tub of water to evaluate despair behavior. Unstressed mice quickly swam to a platform and escaped, but the stressed mice did not make a strong effort to escape and had to be rescued from the tub.

The researchers then compared what the intestinal microbiome looked like in stressed versus unstressed mice. The different species of bacteria comprising the microbiota can be determined by sequencing the DNA in mouse droppings. Each species has a signature DNA sequence that serves as an identifier for that type of bacteria.

The results showed that stress altered the mouse microbiome by reducing a type of bacteria called Lactobacillus. It might have occurred to you that stress could have simply changed the eating habits of the mice, which in turn would affect the composition of the microbiome, but the researchers did not observe any change in eating habits or weight of the stressed mice. Furthermore, when they administered Lactobacillus as a probiotic, the symptoms of depression improved.

Why would stress cause changes in the microbiome? No one knows for sure, but this could be a result of altered brain chemistry making the gut less hospitable to some bacteria. Researchers also noted that intestinal physiology was altered in the stressed animals, which could have played a role in microbiota changes.

When someone consumes a probiotic they are ingesting live bacteria. That concept should no longer gross you out. Probiotics include the so-called "good" bacteria that have been shown to confer health benefits in some studies. These bacteria can be delivered into your body in numerous ways, including food (like yogurt) or pills.  

Does this mean you should rush out to purchase probiotics to battle depression? There are important caveats to studies like this that should be considered. The study was performed in a mouse model of depression, which may not fully represent the condition in humans. The microbiome of controlled laboratory animals is more uniform than humans, who tend to have vastly different bacteria in their guts depending on such things as diet, geography, illness, and age.

However, a 2016 meta-analysis (a study of studies) concluded that “probiotics were associated with a significant reduction in depression [in humans], underscoring the need for additional research on this potential preventive strategy for depression.” While that sounds encouraging, we are far from understanding how certain bacteria may ameliorate depression and whether this affect holds up in diverse patient populations. Probiotics certainly should not replace the more rigorously established treatments for depression recommended by health professionals.

Bill Sullivan is a professor at the Indiana University School of Medicine. Follow him on Twitter @wjsullivan.

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