Antibiotics, Antivirals, and Resistance Mechanisms

Antibiotics are drugs that kill or stop the growth of bacteria, antiviral drugs interfere with viruses, and antibiotic resistance occurs when bacteria evolve to survive drugs that once killed them. In brief: antibiotics do not work against viruses. Resistance spreads by natural selection: when an antibiotic is used, resistant bacteria survive and multiply, and they can pass resistance genes to other bacteria. Vaccination prevents many infections and reduces the need for antibiotics.

Antibiotics changed medicine in the twentieth century, and resistance now threatens to undo this progress. This guide explains how antibiotics work, how antiviral drugs differ, how bacteria become resistant, how vaccination helps, works through a calculation of selection for resistance and corrects the common misunderstandings.

How do antibiotics work?

Antibiotics are substances, made by microorganisms or synthesized, that act against bacteria. They are effective because they target features of bacteria that human cells lack, which makes them selectively toxic. Bactericidal antibiotics kill bacteria, and bacteriostatic antibiotics stop them from multiplying and allow the immune system to clear the infection.

• Inhibition of cell wall synthesis: penicillins and cephalosporins block the formation of peptidoglycan. The weakened wall bursts when water enters by osmosis. Human cells have no cell wall, so they are not affected.
• Inhibition of protein synthesis: tetracyclines and macrolides (such as erythromycin) bind to bacterial 70S ribosomes, which differ from human 80S ribosomes.
• Inhibition of nucleic acid synthesis: fluoroquinolones (such as ciprofloxacin) block bacterial enzymes that copy DNA, and rifampicin blocks RNA polymerase.
• Blocking a metabolic pathway: sulfonamides block the synthesis of folic acid, which bacteria must make but humans obtain from food.

Antibiotics are different from disinfectants and antiseptics, which kill microbes on surfaces or skin and can also damage human cells. A broad-spectrum antibiotic affects many types of bacteria, while a narrow-spectrum antibiotic targets a few. Broad-spectrum drugs also harm useful gut bacteria, which can cause diarrhea or allow infection by Clostridioides difficile.

How do antiviral drugs work?

Viruses use the host cell’s machinery, so it is harder to find drugs that attack them without harming the host. Antiviral drugs target virus-specific steps.

• Blocking entry or release: oseltamivir (Tamiflu) inhibits neuraminidase, an enzyme that helps influenza viruses to leave cells.
• Inhibiting viral genome copying: aciclovir (acyclovir) interferes with the DNA polymerase of herpesviruses. Reverse transcriptase inhibitors and integrase inhibitors are used against HIV.
• Blocking viral assembly: protease inhibitors stop the cutting of viral proteins into functional parts, in HIV and hepatitis C.

Antivirals generally reduce the severity and duration of disease, and are most effective when given early. Some viruses, like HIV, are treated with combinations of drugs to prevent the development of resistance. Viruses can also become resistant, as RNA viruses mutate quickly.

How does antibiotic resistance develop?

Resistance arises by natural selection.

1. Variation: in a large population of bacteria, a few cells carry a random mutation or a gene (often on a plasmid) that protects them from an antibiotic. For example, the gene for beta-lactamase, an enzyme that destroys penicillin.
2. Selection: when the antibiotic is used, sensitive bacteria are killed and resistant ones survive.
3. Reproduction: survivors multiply by binary fission, and with no competition from sensitive bacteria the resistant population grows quickly.
4. Spread: bacteria can pass resistance genes to others, even of different species, by conjugation, transformation or transduction. Resistant bacteria spread between people, especially in hospitals.

Typical mechanisms of resistance include destroying the antibiotic with an enzyme, changing the target, pumping the drug out of the cell with efflux pumps and reducing permeability. MRSA (methicillin-resistant Staphylococcus aureus), multidrug-resistant tuberculosis and carbapenem-resistant bacteria are of special concern. WHO estimates that bacterial antimicrobial resistance was directly responsible for over a million deaths per year in recent studies.

Resistance is promoted by overuse and misuse: prescribing antibiotics for viral infections like colds, not completing the course, using them in livestock as growth promoters and the release of antibiotics into the environment.

Classes of antimicrobial drugs

How does vaccination help?

A vaccine contains a harmless form of a pathogen, or part of it, such as a weakened or killed microbe, a protein or a piece of genetic instruction (as in mRNA vaccines). It trains the immune system to produce antibodies and memory cells without causing the disease. If the person later meets the real pathogen, the immune system responds quickly. Vaccines protect against viruses, for which antibiotics are useless, and against bacteria, which reduces the use of antibiotics and the chance of resistance. Smallpox has been eradicated worldwide through vaccination, with the last natural case in 1977, and polio is close to eradication. The immune response is described in the articles on the immune system.

Worked example: selection for resistance

A population has 10⁹ bacteria, and 1 in 10⁷ carries a resistance mutation. An antibiotic kills 99.99 percent of the sensitive cells but none of the resistant cells.

1. Resistant cells at the start: 10⁹ ÷ 10⁷ = 100 resistant cells. Sensitive cells = 10⁹ − 100 ≈ 10⁹.
2. After treatment: sensitive survivors = 10⁹ × 0.0001 = 10⁵ = 100 000. Resistant cells = 100.
3. Proportion resistant now: 100 ÷ (100 000 + 100) ≈ 0.1 percent. It was 0.00001 percent before (10⁻⁷ of the population), so the proportion has increased by a factor of 10 000.
4. Second round of treatment: sensitive survivors = 100 000 × 0.0001 = 10. Resistant = 100. The proportion resistant = 100 ÷ 110 ≈ 91 percent.

After just two rounds of treatment, the population is mostly resistant. In reality, the immune system and the remaining doses would also kill some cells, so this is a simplified model. It shows the importance of finishing treatment to eliminate infections quickly before resistant mutants can grow, and that the antibiotic itself is the selection pressure.

What can be done about resistance?

• Use antibiotics only when needed (for bacterial infections), and follow the prescribed dose and duration.
• Reduce use in livestock, and improve hygiene and infection control in hospitals.
• Use vaccines to prevent infections.
• Monitor resistance and develop new antibiotics and alternatives, such as bacteriophage therapy.
• Prevent the spread of resistant bacteria through hand hygiene, sanitation and clean water.

How were antibiotics discovered?

Paul Ehrlich developed salvarsan, the first synthetic drug for syphilis, in 1909. Alexander Fleming noticed in 1928 that the mold Penicillium killed bacteria on a culture plate. Howard Florey and Ernst Chain developed penicillin as a medicine in the early 1940s, and Fleming, Florey and Chain shared the 1945 Nobel Prize in Physiology or Medicine. Fleming warned in his Nobel lecture that misuse could lead to resistance, and resistant strains of Staphylococcus were reported in the 1940s. Edward Jenner developed the first vaccine, against smallpox, in 1796.

Which mistakes are common?

Mistake 1: Thinking that antibiotics kill viruses

They do not. Colds and influenza are caused by viruses.

Mistake 2: Saying that a person becomes resistant to antibiotics

The bacteria become resistant, not the person.

Mistake 3: Stopping the course when symptoms improve

Some bacteria may survive, and these may be more resistant. Follow the doctor’s instructions.

Mistake 4: Saying that bacteria “learn” to be resistant

Resistance arises through random mutation and selection, and through gene transfer, not through any decision by the bacteria.