Antibiotics

An antibiotic is a chemical substance — originally produced by a microorganism (e.g. a fungus or another bacterium) — that kills bacteria or inhibits their growth at low concentrations, used to treat bacterial infections.

The history of antibiotics begins with Alexander Fleming in 1928, who noticed that the fungus Penicillium notatum growing on a Petri dish inhibited the growth of Staphylococcus. The active substance was called penicillin. Fleming did not pursue large-scale production, but in the late 1930s Howard Florey and Ernst Chain at Oxford developed methods to purify and produce penicillin in quantity, just in time to save many lives during World War II. Fleming, Florey and Chain shared the 1945 Nobel Prize.

Antibiotics may be:

• Bactericidal — kill bacteria (penicillin, streptomycin, ciprofloxacin).
• Bacteriostatic — inhibit bacterial growth and reproduction, leaving the host immune system to clear them (tetracycline, erythromycin).

Antibiotics differ from antiseptics (which kill microbes on surfaces or skin, e.g. ethanol, iodine) and from antivirals (which target viral enzymes — antibiotics do not work on viruses).

The genius of antibiotics is selective toxicity — they target structures and processes found in bacteria but not in human cells. Without selectivity, an antibiotic would just be a poison. Key bacterial targets and the antibiotics that exploit them:

1. Peptidoglycan cell wall (penicillins, cephalosporins). Bacterial cell walls are made of peptidoglycan (murein) — polysaccharide chains cross-linked by short peptides. The cross-links are made by transpeptidase. β-lactam antibiotics (penicillin, amoxicillin) contain a β-lactam ring that mimics the substrate of transpeptidase and irreversibly inhibits it. Newly forming wall lacks cross-links, weakens, and the bacterium bursts by osmotic lysis (water enters by osmosis because the bacterium has high internal solute). Bactericidal; affects dividing bacteria only. Human cells have no peptidoglycan, so are unaffected.

2. Bacterial 70S ribosome (aminoglycosides, tetracyclines). Bacterial ribosomes are 70S (50S + 30S subunits); human ribosomes are 80S (60S + 40S). Streptomycin and other aminoglycosides bind the 30S subunit; tetracyclines also bind 30S; erythromycin binds 50S. All block protein synthesis. Bacteriostatic or bactericidal. Mitochondrial ribosomes in human cells are 70S, which is why aminoglycosides have some toxicity to humans (ear and kidney).

3. DNA gyrase (quinolones, fluoroquinolones). Ciprofloxacin inhibits bacterial DNA gyrase, an enzyme that supercoils bacterial DNA before replication. Eukaryotes use topoisomerase II, which is structurally different.

4. Folate synthesis (sulfonamides, trimethoprim). Bacteria must synthesise folate; humans get it from the diet. Sulfonamides block bacterial folate synthesis without affecting human cells.

Why antibiotics do not affect viruses. Viruses lack cell walls, ribosomes of their own, DNA gyrase and independent metabolism. They are nothing more than nucleic acid in a protein coat and replicate by hijacking the host's 80S ribosomes. The bacterial targets of antibiotics simply do not exist in viruses. Viral infections require antiviral drugs (e.g. zidovudine for HIV, oseltamivir for influenza) that target specifically viral enzymes.

Viruses are not cells: they are nucleic acid (DNA or RNA) inside a protein capsid, sometimes with a lipid envelope. They have no cell wall, no ribosomes, no DNA gyrase and no metabolism of their own. They replicate by injecting their nucleic acid into a host cell and using the host cell's 80S ribosomes and enzymes to assemble new viral particles.

Because antibiotics target structures unique to bacteria — peptidoglycan walls, 70S ribosomes, bacterial DNA gyrase, bacterial folate synthesis — they have no effect on viruses. A patient with a viral infection (cold, flu, COVID-19, HIV) does not benefit from antibiotics, and being prescribed antibiotics for a viral infection only adds to the selection pressure for resistant bacteria in their gut flora.

Viral infections that need treatment are tackled with antiviral drugs that target specifically viral enzymes:

• Zidovudine, lamivudine, efavirenz — inhibit HIV reverse transcriptase or integrase.
• Oseltamivir (Tamiflu) — inhibits influenza neuraminidase.
• Acyclovir — inhibits herpes virus DNA polymerase.
• Remdesivir, paxlovid — inhibit SARS-CoV-2 polymerase / protease.

Many viral infections have no specific antivirals; we rely on vaccination (prevention) and supportive treatment.

Antibiotic resistance arises by random mutation in a bacterial gene during DNA replication. Crucially, the mutation arises spontaneously, before the antibiotic is encountered — the antibiotic only selects for it. Saying 'bacteria evolve resistance because they are exposed to antibiotics' is Lamarckian and scores zero.

Mechanisms of resistance the mutation may confer:

• Enzymes that destroy the antibiotic. The classic example is β-lactamase (penicillinase), which hydrolyses the β-lactam ring of penicillin, inactivating it.
• Altered target. A mutation that changes the target so the antibiotic no longer binds — e.g. modified penicillin-binding proteins in MRSA so methicillin cannot bind; modified ribosomes so tetracyclines cannot bind.
• Efflux pumps. Membrane proteins that actively pump the antibiotic back out of the bacterium before it can act.
• Reduced permeability. Mutations that reduce the antibiotic's entry into the cell (porin loss in Gram-negative bacteria).

Selection pressure. When the antibiotic is administered, non-resistant bacteria die but resistant bacteria survive. The antibiotic acts as a powerful selection pressure in favour of the resistance allele. Surviving bacteria reproduce by binary fission with a generation time as short as 20-30 minutes — within hours the population is dominated by resistant bacteria (vertical gene transfer).

Resistance spreads by two routes:

Vertical transmission. Resistant bacteria reproduce by binary fission; every offspring inherits the resistance allele. This is the same as inheritance in any asexual organism.

Horizontal transmission via plasmids. Many resistance genes are carried on plasmids — small loops of DNA that exist separately from the bacterial chromosome and can replicate independently. Plasmids can be transferred between bacteria — even between different species — by conjugation: a 'sex pilus' joins two bacteria, the plasmid is replicated and a copy is transferred to the recipient. This horizontal gene transfer means that a resistance gene that arose in one environmental species (e.g. a soil bacterium) can rapidly appear in a pathogenic species (e.g. E. coli, Salmonella).

Some plasmids carry multiple resistance genes — the R-plasmid in E. coli can give resistance to several different antibiotics simultaneously. So a single conjugation event can confer multi-drug resistance.

Two further mechanisms of horizontal transfer:

• Transduction — DNA carried between bacteria by bacteriophages (viruses that infect bacteria).
• Transformation — uptake of free DNA from the environment.

The combined effect of vertical inheritance and rapid horizontal transfer is that resistance spreads through bacterial populations much faster than would be possible by mutation alone.

Human factors accelerate this spread:

• Incomplete courses — stopping early leaves the most-resistant survivors to recover and reproduce.
• Unnecessary prescriptions — antibiotics for viral infections add selection pressure for nothing.
• Over-the-counter sales in countries with poor regulation.
• Agricultural use as growth promoters — continuous low-dose antibiotics in livestock continually select for resistance. Banned in EU since 2006.
• Hospital environment — high antibiotic use, immunocompromised patients, frequent contact → ideal for the spread of MRSA and similar.

MRSA (methicillin-resistant Staphylococcus aureus) is S. aureus that has acquired the mecA gene, encoding a modified penicillin-binding protein with low affinity for methicillin and most other β-lactam antibiotics. MRSA causes serious skin, wound, blood and respiratory infections, particularly in hospitals (hospital-acquired MRSA, HA-MRSA) but also increasingly in the community (CA-MRSA).

Treatment of MRSA requires non-β-lactam antibiotics: vancomycin is the mainstay, but VRSA (vancomycin-resistant S. aureus) has now also appeared in some settings.

Control of MRSA in hospitals depends on:

• Hand hygiene (alcohol gel and hand-washing).
• Screening patients on admission and isolating positive carriers.
• Barrier nursing — gowns, gloves, disinfection of equipment.
• Antibiotic stewardship — narrow-spectrum drugs only where needed.

MDR-TB and XDR-TB. Multi-drug-resistant TB (resistant to at least rifampicin + isoniazid) and extensively drug-resistant TB (also resistant to fluoroquinolones + at least one injectable second-line drug) are growing global problems. They arise from incomplete TB treatment courses and amplify due to airborne transmission. Treatment takes up to 2 years with expensive, toxic second-line drugs.

The WHO estimates that without urgent action, antimicrobial resistance could cause 10 million deaths per year by 2050 — exceeding cancer.

Antibiotic resistance is a global crisis. Strategies to slow it operate at every level — patient, clinician, hospital, policy:

At the patient and clinician level:

• Prescribe only when necessary — never for viral infections (colds, flu, sore throat, COVID-19). Use diagnostic tests where possible.
• Use narrow-spectrum antibiotics based on culture and sensitivity testing — reserve broad-spectrum and last-resort drugs (vancomycin, carbapenems, colistin) for serious cases.
• Patients must complete the full course as prescribed. Stopping early leaves the most-resistant survivors to repopulate.

At the hospital and healthcare system level:

• Strict hygiene — hand-washing between patients, alcohol gel, disinfection of equipment.
• Isolate MRSA-positive patients and use barrier nursing.
• Antibiotic stewardship — formal hospital programmes that monitor and restrict antibiotic prescribing.
• Surveillance — track resistance patterns and adjust empirical treatment.

At the agricultural and policy level:

• Restrict use in livestock — ban antibiotics as growth promoters (EU since 2006).
• Restrict over-the-counter sales in countries where antibiotics are sold without prescription.
• Public education — campaigns to change patient and farmer expectations.

At the research and development level:

• Invest in new antibiotics with novel mechanisms — the development pipeline has been very thin since the 1980s.
• Develop alternative therapies — bacteriophage therapy, antibody-based treatments, antimicrobial peptides.
• Use vaccines to reduce bacterial disease (pneumococcal, Hib, typhoid).

International cooperation: the WHO Global Action Plan on Antimicrobial Resistance (2015) coordinates national and global responses; 'Antibiotic Awareness Week' is held annually each November.