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How Do Antibiotics Work?

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How do antibiotics work?

Drew Smith:

Antibiotics have been around for a long time now, and we know which bacterial proteins they attack. ß-lactams like amoxicillin inhibit the enzyme that crosslinks peptidoglycans in bacterial cell walls. Fluoroquinolones like ciprofloxacin bind DNA topoisomerases and prevent them from coiling and uncoiling bacterial chromosomes. But so what? How does blocking these processes actually kill bacterial cells?

It turns out that we really don’t know a lot about how antibiotics actually kill bacteria, although we are beginning to get some clues.

One of these clues is that some antibiotics require bacterial protein synthesis in order to be effective: inhibition of protein synthesis reduces the lethality of ß-lactams, for instance. Simply blocking cell wall synthesis does not lead to rapid and complete killing of bacteria—something more is required.

Further research shows that antibiotics induce bacterial stress responses, and it is these responses, rather than the immediate activity of the antibiotics, which lead to cell death. In fact, a unified theory of antibiotic-induced cell death is beginning to emerge in which several classes of antibiotics work through a common mechanism.

Essentially, the stress response of cells to antibiotics causes disregulation of the carefully controlled membrane electrical potential. All cells generate chemical energy by pumping positively charged protons out of the cell, leaving an excess of negatively charged electrons within. The electrical potential created by this mechanism is enormous, as Nick Lane has pointed out; at the cellular scale, it is equivalent to a bolt of lightning.

Normally this power is used to turn a turbine-like molecular assembly (ATP synthase) that converts electrical energy into chemical energy. But when the flow of power is disrupted, a storm of highly reactive electrons is let loose in the cell, where they destroy everything—proteins, DNA, RNA.

We don’t yet understand all the steps that make this happen. That blue box in the figure which says “Metabolic Feedback” is really a black box. But this research should surely lead to new strategies for designing antibiotics and suppressing the evolution of antibiotic resistance.

This post originally appeared on Quora. Click here to view.

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Health
How Promoting Handwashing Got One 19th Century Doctor Institutionalized
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Regardless of how often we actually do it, it's common knowledge that washing our hands before eating, after coughing, and after using the bathroom is good for us. But the connection between handwashing and health wasn't always accepted as fact. As Danielle Bainbridge explains in the PBS web series Origin of Everything, the first doctor to campaign for cleanliness in hospitals was not only shunned by other medical professionals, but ended up in an insane asylum.

Prior to the 19th century, handwashing primarily existed in the context of religious ceremonies and practices. It plays a role in Christianity, Islam, Judaism, Sikhism, and Buddhism in some form or another. But washing up to stop the spread of disease wasn't really a thing for most of history. People weren't aware of germs, so instead of microbes, they blamed illness on everything from demons to bad air.

Then, in 1846, a Hungarian doctor named Ignaz Semmelweis made a breakthrough observation. He noticed that women giving birth with the help of midwives were less likely to die than those treated by doctors. He determined that because doctors were also performing autopsies on victims of puerperal fever (a bacterial infection also known as childbed fever), they were somehow spreading the disease to their other patients. Semmelweis started promoting handwashing and instrument sterilization in his clinic, and the spread of puerperal fever dropped as a result.

Despite the evidence to support his theory, his peers in the medical community weren't keen on the idea of blaming patient deaths on doctors. Partly due to his commitment to the controversial theory, Semmelweis was shunned from his field. He suffered a mental breakdown and ended up in a mental hospital, where he died a few weeks later.

Germ theory did eventually become more mainstream as the century progressed, and washing hands as a way to kill unseen pathogens started gaining popularity. Even so, it wasn't until the 1980s that the CDC released the first official guidelines instructing people on best handwashing practices.

If this story suddenly has you in the mood to practice good hygiene, here's the best way to wash your hands, according to experts.

[h/t Origin of Everything]

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History
How an Early Female Travel Writer Became an Immunization Pioneer
Lady Mary Wortley Montagu by A. Devéria
Lady Mary Wortley Montagu by A. Devéria

Lady Mary Wortley Montagu was a British aristocrat, feminist, and writer who was famed for her letters. If that were all she did, she would be a slightly obscure example of a travel writer and early feminist. But she was also an important public health advocate who is largely responsible for the adoption of inoculation against smallpox—one of the earliest forms of immunization—in England.

Smallpox was a scourge right up until the mid-20th century. Caused by two strains of Variola virus, the disease had a mortality rate of up to 35 percent. If you lived, you were left with unsightly scars, and possible complications such as severe arthritis and blindness.

Lady Montagu knew smallpox well: Her brother died of it at the age of 20, and in late 1715, she contracted the disease herself. She survived, but her looks did not; she lost her eyelashes and was left with deeply pitted skin on her face.

When Lady Montagu’s husband, Edward Wortley Montagu, was appointed ambassador to Turkey the year after her illness, she accompanied him and took up residence in Constantinople (now Istanbul). The lively letters she wrote home described the world of the Middle East to her English friends and served for many as an introduction to Muslim society.

One of the many things Lady Montagu wrote home about was the practice of variolation, a type of inoculation practiced in Asia and Africa likely starting around the 15th or 16th century. In variolation, a small bit of a pustule from someone with a mild case of smallpox is placed into one or more cuts on someone who has not had the disease. A week or so later, the person comes down with a mild case of smallpox and is immune to the disease ever after.

Lady Montagu described the process in a 1717 letter:

"There is a set of old women, who make it their business to perform the operation, every autumn, in the month of September, when the great heat is abated. People send to one another to know if any of their family has a mind to have the small-pox: they make parties for this purpose, and when they are met (commonly fifteen or sixteen together) the old woman comes with a nuts-hell full of the matter of the best sort of small-pox, and asks what veins you please to have opened. She immediately rips open that you offer to her with a large needle (which gives you no more pain than a common scratch), and puts into the vein as much matter as can lye upon the head of her needle, and after that binds up the little wound with a hollow bit of shell; and in this manner opens four or five veins. . . . The children or young patients play together all the rest of the day, and are in perfect health to the eighth. Then the fever begins to seize them, and they keep their beds two days, very seldom three. They have very rarely above twenty or thirty in their faces, which never mark; and in eight days' time they are as well as before their illness."

So impressed was Lady Montagu by the effectiveness of variolation that she had a Scottish doctor who worked at the embassy, Charles Maitland, variolate her 5-year-old son in 1718 with the help of a local woman. She returned to England later that same year. In 1721, a smallpox epidemic hit London, and Montagu had Maitland (who by then had also returned to England) variolate her 4-year-old daughter in the presence of several prominent doctors. Maitland later ran an early version of a clinical trial of the procedure on six condemned inmates in Newgate Prison, who were promised their freedom if they took part in the experiment. All six lived, and those later exposed to smallpox were immune. Maitland then repeated the experiment on a group of orphaned children with the same results.

A painting of Lady Mary Wortley Montagu with her son, Edward Wortley Montagu, and attendants
Lady Mary Wortley Montagu with her son, Edward Wortley Montagu, and attendants
Jean-Baptiste Vanmour, Art UK // CC BY-NC-ND

But the idea of purposely giving someone a disease was not an easy sell, especially since about 2 or 3 percent of people who were variolated still died of smallpox (either because the procedure didn’t work, or because they caught a different strain than the one they had been variolated with). In addition, variolated people could also spread the disease while they were infectious. Lady Montagu also faced criticism because the procedure was seen as “Oriental,” and because of her gender.

But from the start, Lady Montagu knew that getting variolation accepted would be an uphill battle. In the same letter as her first description of the practice, she wrote:

"I am patriot enough to take pains to bring this useful invention into fashion in England; and I should not fail to write to some of our doctors very particularly about it, if I knew any one of them that I thought had virtue enough to destroy such a considerable branch of their revenue for the good of mankind. But that distemper is too beneficial to them, not to expose to all their resentment the hardy wight that should undertake to put an end to it. Perhaps, if I live to return, I may, however, have courage to war with them."

As promised, Lady Montagu promoted variolation enthusiastically, encouraging the parents in her circle, visiting convalescing patients, and publishing an account of the practice in a London newspaper. Through her influence, many people, including members of the royal family, were inoculated against smallpox, starting with two daughters of the Princess of Wales in 1722. Without her advocacy, scholars say, variolation might never have caught on and smallpox would have been an even greater menace than it was. The famed poet Alexander Pope said that for her, immortality would be "a due reward" for "an action which all posterity may feel the advantage of," namely the "world’s being freed from the future terrors of the small-pox."

Variolation was performed in England for another 70 years, until Edward Jenner introduced vaccination using cowpox in 1796. Vaccination was instrumental in finally stopping smallpox: In 1980, it became the first (and so far, only) human disease to be completely eradicated worldwide.

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