Antibiotic
An antibiotic is a substance active against bacteria, and the word itself carries a strange contradiction. It comes from the Greek roots anti, meaning against, and bios, meaning life. Yet these life-opposing compounds have saved more lives than almost any class of medicine in history. They kill bacteria or stop their growth, but they do nothing against the viruses behind a common cold or influenza, and nothing against fungi. The story has stranger corners still. Ancient Sudanese bodies carry the chemical fingerprint of antibiotics in their bones. A French physician once wrote that intervening in the war between bacteria might offer the greatest hopes for therapeutics. And today the World Health Organization warns of a threat already happening in every region of the world. How did humans stumble onto these compounds, who turned them into medicine, and why are they now failing?
Northern Sudan holds the oldest known trace of antibiotic use, dating to ancient Sudanese societies between 350 and 550 CE. Chemical analysis of Nubian skeletons revealed consistent, high levels of tetracycline, a powerful antibiotic, locked into the bone. Researchers concluded the people were brewing beverages from grain fermented with Streptomyces, a bacterium that naturally produces tetracycline. As one assessment put it, given the amount of tetracycline there, they had to know what they were doing.
Moldy bread appears again and again across the ancient world as a folk treatment for infection. Later evidence points to its topical use in Egypt, China, Serbia, Greece, and Rome. Mixtures with antimicrobial properties were described over 2,000 years ago, and many ancient cultures selected specific molds and plants to treat wounds. The first person to directly document the use of molds against infection was John Parkinson, who lived from 1567 to 1650. These were observations, not understandings. The science of why mold fought infection would wait centuries, and when it arrived, it began not with mold at all but with dyes.
Paul Ehrlich, working in Germany in the late 1880s, noticed that certain dyes would color human, animal, or bacterial cells while others did not. From that observation he reasoned that a chemical might be built to bind to and kill bacteria without harming the human host. After screening hundreds of dyes against various organisms, his team found success with the 606th compound in their series. Ehrlich worked alongside Alfred Bertheim and the Japanese bacteriologist Sahachiro Hata in the search for a syphilis treatment.
In 1910, Ehrlich and Hata announced drug 606 at the Congress for Internal Medicine at Wiesbaden. The Hoechst company began marketing it late that year under the name Salvarsan, later known as arsphenamine, and it became the standard syphilis treatment in the first half of the 20th century. Ehrlich had already received the Nobel Prize in Physiology or Medicine in 1908 for his work in immunology, and Hata was later nominated for Nobel Prizes in chemistry and in medicine.
The next leap came from a research team led by Gerhard Domagk at the Bayer Laboratories of the IG Farben conglomerate. In 1932 or 1933 they developed Prontosil, the first sulfonamide and the first systemically active antibacterial drug. It worked against Gram-positive cocci but not against enterobacteria. Its active drug, sulfanilamide, could not be patented because it had already been used in the dye industry for years. Domagk received the 1939 Nobel Prize in Physiology or Medicine, and the discovery opened the era of antibacterials.
Louis Pasteur and Robert Koch first described antibiosis in 1877, observing that an airborne bacillus could inhibit the growth of Bacillus anthracis. Pasteur wrote that intervening in the antagonism between bacteria might offer perhaps the greatest hopes for therapeutics. In 1874 the physician Sir William Roberts noted that cultures of the mould Penicillium glaucum, used in making some blue cheeses, stayed free of bacterial contamination. Vincenzo Tiberio published on the antibacterial power of mold extracts in 1895.
Ernest Duchesne, a doctoral student, submitted a dissertation in 1897 proposing that bacteria and moulds wage a perpetual battle for survival. He observed that Penicillium glaucum eliminated E. coli in shared culture, and that animals given lethal doses of typhoid bacilli alongside the mould did not contract typhoid. His army service cut his research short, and he later died of tuberculosis, a disease now treated by antibiotics.
The breakthrough belongs to Sir Alexander Fleming, who lived from 1881 to 1955. In 1928, working on a culture of disease-causing bacteria, he noticed spores of a green mold, Penicillium rubens, on one of his plates. The mould had killed or prevented the growth of the surrounding bacteria. Fleming named the antibacterial substance penicillin, but he could not develop it further without trained chemists. That work fell to others, and it would take a world war to make it matter.
Ernst Chain, Howard Florey, and Edward Abraham purified the first penicillin, penicillin G, in 1942. It did not become widely available outside the Allied military before 1945. Norman Heatley developed a back extraction technique to purify penicillin in bulk, and Abraham first proposed its chemical structure in 1942. Dorothy Crowfoot Hodgkin confirmed that structure in 1945. Unlike the synthetic sulfonamides, purified penicillin kept working even in the presence of biological matter such as pus, and it carried low toxicity in humans. For developing penicillin into a therapeutic drug, Chain and Florey shared the 1945 Nobel Prize in Medicine with Fleming.
Florey credited René Dubos with pioneering the deliberate, systematic search for antibacterial compounds. In 1939, as World War II began, Dubos reported tyrothricin, the first naturally derived antibiotic, drawn from Bacillus brevis. It was a compound of 20% gramicidin and 80% tyrocidine and became one of the first commercially manufactured antibiotics, effective on wounds and ulcers during the war. Both gramicidin and tyrocidine, however, proved too toxic for systemic use. Research from this period was not shared between the Axis and Allied powers, and access stayed limited into the Cold War.
Most antibiotics target bacterial functions or growth processes, and they are grouped by mechanism, chemical structure, or spectrum of activity. Those that attack the bacterial cell wall, like penicillins and cephalosporins, or the cell membrane, like polymyxins, kill bacteria outright. So do drugs that interfere with essential enzymes, such as rifamycins, quinolones, and sulfonamides. Protein synthesis inhibitors, including macrolides and tetracyclines, usually only stop further growth, with bactericidal aminoglycosides as the exception.
Narrow-spectrum antibiotics target specific types of bacteria, such as gram-negative or gram-positive, while broad-spectrum drugs hit a wide range. When a pathogen is suspected but unidentified, doctors begin empiric therapy with a broad-spectrum drug while waiting on laboratory results that can take several days. Once the microbe is known, definitive therapy with a narrow-spectrum antibiotic can begin, which lowers cost and toxicity.
Combination therapy pairs two or more antibiotics, a tactic used in tuberculosis to delay resistance. Fosfomycin has the highest number of synergistic combinations and is almost always used as a partner drug. Not every pairing helps: chloramphenicol and tetracyclines are antagonists to penicillins. Most antibacterial compounds are small molecules weighing less than 1000 daltons, and roughly 70 to 80% of antibiotics in current use derive from the actinomycetes.
Antimicrobial resistance is a naturally occurring process, driven largely by the misuse and overuse of antimicrobials, even as many people worldwide lack access to essential ones. Nearly 5 million deaths each year are associated with AMR globally, and global deaths attributable to it numbered 1.27 million in 2019. The Luria-Delbrück experiment demonstrated antibacterial selection for resistant strains back in 1943. Penicillin and erythromycin, once highly effective, have lost ground as bacterial strains adapted.
Resistance spreads not only through inheritance but through horizontal gene transfer, where plasmids carrying resistance genes move between bacterial strains or species. A single such plasmid can carry several resistance genes at once. Strains that resist many drugs are sometimes called superbugs. Nearly half a million new cases of multidrug-resistant tuberculosis are estimated worldwide each year. The enzyme NDM-1 confers resistance to a broad range of beta-lactam antibacterials, and the UK Health Protection Agency stated that most isolates with it resist all standard intravenous antibiotics for severe infections.
On the 26th of May 2016, an E. coli superbug resistant to colistin, described as the last line of defence, was identified in the United States. Even anaerobic bacteria once thought low-risk now show high resistance, with Bacteroides resistance to penicillin reported to exceed 90%. As The ICU Book puts it, the first rule of antibiotics is to try not to use them, and the second rule is to try not to use too many of them.
From 1935 to 1968, twelve new classes of antibiotic reached medical use, but only two new classes arrived between 1969 and 2003. After that 40-year break, four new classes entered clinical use in the late 2000s and early 2010s: cyclic lipopeptides like daptomycin, glycylcyclines like tigecycline, oxazolidinones like linezolid, and lipiarmycins like fidaxomicin. According to the WHO, fifty-one new therapeutic antibiotic entities were in phase 1 to 3 clinical trials as of May 2017.
In the United States, the ADAPT Act was introduced to fast track antibiotic development against superbugs, letting the FDA approve drugs for life-threatening infections based on smaller clinical trials. Allan Coukell of The Pew Charitable Trusts said allowing developers to rely on smaller datasets would make trials more feasible. France ran an Antibiotics are not automatic campaign starting in 2002, which sharply cut unnecessary prescriptions, especially in children. The European Union has banned antibiotics as growth-promotional agents since 2003.
Beyond chemistry, researchers are testing biology itself. Phage therapy infects bacterial pathogens with viruses that target single strains without disturbing the gut microbiota. Fecal microbiota transplants for C. difficile infection report cure rates around 90%. Antisense RNA can silence the S. aureus mecA gene that makes the bacterium methicillin-resistant. And CRISPR-Cas9, the bacterial defense system discovered in the early 2000s, can be reprogrammed to target a microbe's own resistance genes, turning a bacterium's immune machinery against itself.
Common questions
What does the word antibiotic mean and where does it come from?
Antibiotic literally means opposing life, from the Greek roots anti, meaning against, and bios, meaning life. The term was first used in 1942 by Selman Waksman and his collaborators to describe a substance produced by a microorganism that is antagonistic to the growth of other microorganisms.
Who discovered penicillin and when?
Sir Alexander Fleming discovered penicillin in 1928 after noticing that spores of a green mold, Penicillium rubens, killed or prevented the growth of bacteria on one of his culture plates. He named the antibacterial substance penicillin but could not develop it further without trained chemists.
Why are antibiotics not effective against viruses or fungi?
Antibiotics are active against bacteria, not against viruses such as those causing the common cold or influenza, and not against fungi. Drugs that inhibit viruses are called antivirals, and drugs that inhibit fungi are called antifungals.
What is the oldest known use of antibiotics?
The earliest known use of antibiotics was found in northern Sudan, where ancient Sudanese societies between 350 and 550 CE consumed antibiotics as part of their diet. Chemical analysis of Nubian skeletons showed high levels of tetracycline, likely from beverages brewed with grain fermented with the bacterium Streptomyces.
How many deaths are caused by antimicrobial resistance each year?
Nearly 5 million deaths each year are associated with antimicrobial resistance globally. Global deaths directly attributable to antimicrobial resistance numbered 1.27 million in 2019.
How do antibiotics kill or stop bacteria?
Antibiotics target bacterial functions or growth processes. Drugs targeting the cell wall, cell membrane, or essential enzymes kill bacteria, while protein synthesis inhibitors such as macrolides and tetracyclines usually only inhibit further growth. Narrow-spectrum antibiotics target specific bacteria while broad-spectrum antibiotics affect a wide range.
What new approaches are being developed to fight antibiotic resistance?
Researchers are developing phage therapy, which infects bacteria with viruses, fecal microbiota transplants with cure rates around 90% for C. difficile, antisense RNA that silences resistance genes such as the S. aureus mecA gene, and reprogrammed CRISPR-Cas9 systems that target bacterial resistance and virulence genes.