How Do Antibiotics Work, and Why Do Bacteria Stop Responding?
By the BrainSnail editorial team. How these articles are written and checked, and how to tell us when one is wrong.
An antibiotic is a poison with excellent aim. It kills bacteria inside a human body without killing the body, and it manages that by attacking parts of the bacterial cell that human cells do not possess: a rigid outer wall, a different kind of protein factory, a different way of copying DNA. That selectivity is why antibiotics turned once-fatal infections into a week of tablets, and the fact that bacteria evolve is why the advantage is being lost.
The first one was an accident
In 1928 Alexander Fleming returned from holiday to find a mould growing on a dish of bacteria in his London laboratory, with a clear ring around it where the bacteria had died. The mould was a Penicillium and the substance it secreted was named penicillin, but Fleming could not purify it and moved on. It took Howard Florey and Ernst Chain in Oxford, in 1940, to produce enough to treat a patient, and American factories in the war to make it in quantity. By 1945 it was saving thousands of wounded soldiers, and the three shared the Nobel Prize.
Penicillin's trick, worked out later, is that it blocks an enzyme bacteria use to build their cell wall. A growing bacterium keeps making wall and, unable to finish it, bursts under its own internal pressure. Human cells have no wall, so the drug passes them by.
The main ways of killing a bacterium
Every antibiotic in use exploits one of a handful of differences between bacterial and human cells:
- •Breaking the wall: penicillins and cephalosporins stop the wall being built; vancomycin binds its building blocks
- •Jamming the protein factory: bacterial ribosomes differ from ours, and tetracyclines, macrolides such as erythromycin, and aminoglycosides bind them and halt protein production
- •Blocking DNA copying: fluoroquinolones such as ciprofloxacin trap the enzyme that unwinds bacterial DNA
- •Starving them of folate: sulphonamides and trimethoprim block a vitamin pathway bacteria must run for themselves and humans get from food
- •Wrecking the membrane: polymyxins punch holes in the outer membrane, a last resort because they damage human kidneys too
Why they do nothing against a cold
Viruses are not cells. They have no wall, no ribosome and no metabolism of their own; they are packages of genetic material that hijack the machinery of the cells they infect. There is nothing in a virus for an antibiotic to attack, and taking one for a cold, flu or COVID-19 does no good and some harm, since every dose also kills off the harmless bacteria in the gut and gives any resistant survivors room to grow. Antiviral drugs exist and work on different principles, blocking the enzymes viruses bring with them or the receptors they use to enter cells.
Most sore throats, coughs and ear infections are viral, which is why doctors now hold back antibiotics for them, and why the pressure from patients to prescribe anyway is one of the drivers of the problem in the next section.
How resistance happens
Bacteria divide every twenty minutes or so and mutate as they go, so in any large population a few cells will by chance carry a change that blunts an antibiotic: an enzyme that chops the drug up, a pump that expels it, a slightly altered target it no longer fits. In the presence of the drug those few survive while their neighbours die, and within days the survivors are the population. Fleming warned of exactly this in his Nobel lecture in 1945, describing a man who took too little penicillin, bred resistant microbes and passed them to his wife.
Worse, bacteria trade genes. Resistance genes often sit on small loops of DNA called plasmids that can pass from one bacterium to another, including between different species, so a resistance that evolves in a harmless gut microbe can be handed to a dangerous one. Hospitals, where sick people, antibiotics and bacteria are all concentrated, are where it spreads fastest. MRSA, the resistant staphylococcus that haunts surgical wards, carries a gene that makes a wall-building enzyme penicillins cannot bind, and it appeared within two years of methicillin's introduction in 1959.
Slowing it down
Resistance cannot be stopped, only slowed, and the methods are mostly about reducing the selection pressure. Prescribing antibiotics only for bacterial infections, and choosing the narrowest drug that will work, gives resistant strains fewer chances. Finishing a course was the old advice; the newer view is that the right length is whatever clears the infection, and that longer courses breed more resistance rather than less. Around two thirds of the world's antibiotics are given to farm animals, mostly to speed growth, and several countries have now banned that use.
The pipeline of new drugs has been thin for decades, because an antibiotic that must be used sparingly is a poor investment for the company that develops it, and governments have begun paying for new ones by subscription rather than by the dose. Vaccines reduce the infections that need treating in the first place. And bacteriophages, viruses that prey on bacteria, are being revived as a treatment a century after they were first tried. The WHO counts antimicrobial resistance among the ten greatest threats to global health, and the count of deaths directly caused by resistant infections is already over a million a year.
The takeaway
Antibiotics kill bacteria by attacking their cell walls, their ribosomes, their DNA-copying enzymes or their metabolism, none of which exist in the same form in human cells, and they do nothing to viruses because viruses have none of those things. Bacteria evolve resistance by mutation and by swapping genes, and slowing that down means using the drugs less and more precisely while new ones are found.