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

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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