Antibiotics

An antibiotic is a chemical substance produced by a living organism, generally a microorganism, that is detrimental to other microorganisms. Antibiotics commonly are produced by soil microorganisms, and they probably represent a means by which organisms in a complex environment such as soil control the growth of competing microorganisms. Antibiotics came into worldwide prominence with the introduction of penicillin in 1941 and since then have revolutionized the treatment of bacterial infections in humans and other animals.

Alexander Fleming was a Scottish bacteriologist, born in 1881 at Lochfield Farm near Darvel in Ayrshire, Scotland, and is best known for his discovery of penicillin. On 3 September 1928 he noticed that a culture plate of Staphylococcus aureus on which he had been working had become contaminated by a fungus. In September 1928, at St Mary's Hospital Medical School, London, he observed stray mould growing on a plate of bacteria, and around the Penicillium mould lay a clear area where the bacteria had been killed, which led him to name the substance penicillin.

The discovery is dated to September 1928 and attributed to Fleming at St Mary's Hospital Medical School, London. Penicillins fall into two groups: the naturally occurring penicillins formed during mold fermentation, and the semisynthetic penicillins in which 6-aminopenicillanic acid is altered in various ways. Penicillin G is a narrow-spectrum agent.

Florey and Chain began work on penicillin in 1939 and quickly confirmed Fleming's findings before beginning to purify the substance. Howard Walter Florey, Baron Florey, was an Australian pathologist born in Adelaide in 1898 who, with Ernst Boris Chain, isolated and purified penicillin for general clinical use.

At the time of the award Sir Alexander Fleming was affiliated with London University in London, United Kingdom.

In the early 1900s the German physician Paul Ehrlich set out to find chemical compounds that could kill infectious microbes without harming the patient, and in 1909 his assistant Sahachiro Hata found Compound 606, which targeted the bacterium Treponema pallidum and was marketed under the name Salvarsan to treat syphilis. Gerhard Domagk was awarded the Nobel Prize in Medicine in 1939 for his work with prontosil and sulfanilamide, the active breakdown product of prontosil in the body. Sulfanilamide was the first synthetic antimicrobial created and served as the foundation for the development of a family of sulfa drugs. After thousands of years in which societies relied on traditional medicine, the first half of the 20th century brought an era of strategic drug discovery.

Howard Florey came to Oxford in 1935 as the newly appointed Professor of Pathology, arriving to state of the art but largely empty labs in the new Sir William Dunn School. Mellanby's train broke down on the way to the board meeting, but he arrived before the meeting ended and persuaded the board differently from its initial choice, and Florey soon recruited the German émigré chemist Ernst Chain from Cambridge. In 1939 Florey concentrated on penicillin while surveying other naturally occurring antibacterial substances, and with Chain and others he demonstrated its curative properties in human studies and developed methods for its production.

Heatley first devised the cylinder-plate diffusion technique, a reliable and sensitive assay for penicillin that was later adopted as the standard assay for antibiotic activity. He suggested extracting from organic solvents a stable salt of penicillin that was soluble in water, and this formed the basis of an early counter-current distribution apparatus he devised and built. The mould was first grown as a surface culture in bedpans, and when bedpans with lids became unobtainable in England during the war Heatley designed a flat-bottomed ceramic vessel that could be stacked.

Two groups of mice were infected with a fatal dose of Streptococcus, and while all the control animals died rapidly, some animals treated with penicillin survived for long periods. Gardner, Reader in Bacteriology at the Dunn School, showed that bacteria initially sensitive to penicillin could rapidly acquire resistance to it in vitro. By February 1941 Florey felt he had enough penicillin to begin trials in humans and enlisted Charles Fletcher at the Radcliffe Infirmary in Oxford, where the first patient Albert Alexander was treated with penicillin.

Although the therapeutic potential of penicillin was recognized in the United Kingdom, the United States played the major role in developing large-scale production during World War II. Ten days after the Japanese attack on Pearl Harbor in December 1941 the companies Pfizer, Lilly, Merck and Squibb agreed to cooperate in scaling up penicillin production. Penicillin research began in July 1941 at a Department of Agriculture laboratory in Peoria, Illinois, where scientists increased the yield by changing the sugar fed to the mold and adding corn-steep liquor, a by-product of corn milling.

Sir Alexander Fleming held a one-third share of the 1945 Nobel Prize in Physiology or Medicine. Ernst Boris Chain and Sir Howard Walter Florey each received a one-third share of the 1945 Nobel Prize in Physiology or Medicine.

The introduction of penicillin in the 1940s began the era of antibiotics and has been recognized as one of the greatest advances in therapeutic medicine. Before penicillin there was no effective treatment for infections such as pneumonia, gonorrhea or rheumatic fever, and hospitals were full of people with blood poisoning from a cut or a scratch.

In the 1940s Selman Waksman, a prominent soil microbiologist at Rutgers University, led a research team that discovered several antimicrobials, including actinomycin, streptomycin, and neomycin. The vast majority of antimicrobial classes in use today were isolated during the golden era of antibiotic discovery, mainly from soil Actinomyces, and further exploration of that niche has not produced novel drug classes in more than 20 years.

Antibacterial agents are commonly grouped by the cellular process they interrupt, and the resulting classes differ as much in their spectrum of activity as in their chemistry. Some act on the construction of the bacterial cell wall, others on the machinery of protein synthesis, others still on nucleic acid function or on the integrity of the membrane. The table below sets out the principal classes, their representative members, and the mechanisms attributed to them.^{1314.3 Mechanisms of Antibacterial Drugs (Microbiology) · OpenStax, Rice University ↗}

Antibiotics can be categorized by their spectrum of activity as narrow-, broad-, or extended-spectrum agents, and narrow-spectrum agents such as penicillin G affect primarily gram-positive bacteria. Penicillins may be divided into the naturally occurring penicillins formed during mold fermentation and the semisynthetic penicillins in which 6-aminopenicillanic acid is altered in various ways. Adding an amino group to penicillin G created the aminopenicillins ampicillin and amoxicillin, which have increased spectrum of activity against more gram-negative pathogens. Methicillin is a semisynthetic penicillin that was developed to address the spread of enzymes called penicillinases that were inactivating the other penicillins.

Antimicrobial resistance occurs when bacteria, viruses, fungi and parasites do not respond to antimicrobial medicines. Some bacteria are naturally resistant to certain antibiotics, known as intrinsic or inherent resistance, while acquired resistance occurs when normally susceptible bacteria become resistant through genetic changes. Because resistant bacteria survive in the presence of the antibiotic and continue to multiply, the infections they cause last longer and can even result in death. Some strains of previously susceptible bacteria such as Staphylococcus developed resistance to the naturally occurring penicillins by producing β-lactamase, an enzyme that destroys the antimicrobial action of the drug.

Strains of Staphylococcus aureus develop resistance to methicillin, known as MRSA, through the acquisition of a new low-affinity penicillin-binding protein rather than by structurally altering their existing PBPs. This new low-affinity protein provides resistance to methicillin and to virtually all β-lactam drugs, except the newer fifth-generation cephalosporins designed specifically to kill MRSA.

Bacteria evade antimicrobial drugs through several distinct routes, and a single pathogen may employ more than one. The mechanisms catalogued below differ in where they act: some keep the drug from ever reaching its target, while others disable the molecule itself or blunt the target's response to it.^{1614.5 Drug Resistance (Microbiology) · OpenStax, Rice University ↗}

Several important factors can accelerate the evolution of drug resistance, including the overuse and misuse of antimicrobials, inappropriate use, subtherapeutic dosing, and patient noncompliance with the recommended course of treatment. Exposure to an antimicrobial can select for chromosomal mutations that are transferred vertically to subsequent generations, while many resistance genes are found on plasmids or in transposons and can be transferred between microbes through horizontal gene transfer. Overuse of antimicrobials, inappropriate prescribing of antibiotics and misuse for incorrect treatment indications are considered major contributing factors to AMR.

Phylogenetic analysis suggests the long-term presence in nature of genes conferring resistance to several classes of antibiotics well before the antibiotic era.

Antimicrobial resistance is an urgent global public health threat that was associated with nearly 5 million deaths worldwide in 2019 and killed at least 1.27 million people. More than 35,000 people die each year as a result of antimicrobial-resistant infections, according to CDC's 2019 Antibiotic Resistance Threats Report. By 2050 antimicrobial resistance is projected to cause 10 million deaths annually, making it a serious global threat.

Only 5 novel classes of antibiotics have been marketed since 2000, and the period after 1987 is called the antibiotic discovery void, a decline worsened by major pharmaceutical companies exiting antibacterial R&D.

On average the cost of developing an antibiotic is around US$1.2 billion, while stewardship practices limit its use so that sales come to about US$100 million or less, roughly a 10-fold lower value.

The priority pathogen list was drawn up to guide and promote research and development of new antibiotics and to address growing global resistance to antimicrobial medicines. The WHO list is divided into three categories according to how urgently new antibiotics are needed: critical, high and medium priority. The most critical group of the WHO list includes multidrug-resistant bacteria such as Acinetobacter, Pseudomonas and various Enterobacteriaceae, among them Klebsiella, E. coli, Serratia and Proteus, which pose a particular threat in hospitals and to patients whose care requires devices such as ventilators. Bacteria in the critical group have become resistant to a large number of antibiotics, including carbapenems and third generation cephalosporins, the best available antibiotics for treating multidrug-resistant bacteria.

WHO leads global efforts to prevent and control antimicrobial resistance in humans through the Global action plan on antimicrobial resistance covering 2026 to 2036 and aiming to preserve the ability to treat human, animal and plant infections through a One Health approach.

• September 1928
  A stray mould on a culture plate
  At St Mary's Hospital Medical School, Alexander Fleming noticed stray mould growing on a plate of bacteria; around the Penicillium mould lay a clear area where the bacteria had been killed, and he named the substance penicillin.^{3Penicillin: the Oxford story · University of Oxford ↗}
• 1939
  Florey turns to penicillin
  While surveying other naturally occurring antibacterial substances, Howard Florey concentrated on penicillin, and with Ernst Chain and others demonstrated its curative properties in human studies and developed methods for its production.^{5Howard Walter Florey, Baron Florey | Penicillin, Nobel Prize, Pathologist · Encyclopaedia Britannica ↗}