The History of Antibiotics

Introduction
What are antibiotics?
History of antibiotics
Commencement of the antibiotic era
First clinical use of antibiotics
The golden age of antibiotic discovery
Developments in antibiotic discovery  
References
Further reading

Antibiotics are medicines used to treat bacterial infections. Traces of antibiotics were found in human skeletons from ancient times dating back to 350 – 550 CE. In the ancient Egyptian era, molds and plant extracts were used to treat infections. However, until the 19^th century, it was not known that such infections were caused by microbes, particularly, bacteria.

What are antibiotics?

Antibiotics treat bacterial infections by killing bacteria or inhibiting bacterial growth inside the body. Antibiotics may be administered orally (pills, capsules, liquids), topically (cream, ointment, spray), or intravenously.

Antibiotics are not routinely prescribed for mild infections, chest infections, ear infections, and sore throats. In addition, antibiotics do not treat viral infections, including the common cold and influenza. Frequent use or inappropriate use of antibiotics can lead to antibiotic resistance. In the United States, about 2 million infections are caused by antibiotic-resistant bacteria annually, leading to 23,000 deaths.

History of antibiotics

Before the discovery of antibiotics, infectious diseases were one of the leading causes of morbidity and mortality among humans. Before the commencement of the modern antibiotic era (more than 2000 years ago), microbes that produce antibiotics were used as interventions to treat infectious diseases in Serbia, China, Greece, and Egypt. The Eber’s papyrus, an Egyptian medical papyrus dated 1550 BC, is the oldest document describing the use of moldy bread and medicinal soils in treating infections. Similarly, traces of tetracycline, an antibody with chelating effects, were found in human bones collected from the Dakhleh Oasis, Egypt.

Phylogenetic reconstruction analysis has identified the persistent presence of several antibiotic-resistant genes since ancient times. Phylogenetic analysis of β-lactamase and housekeeping genes has revealed that these genes are highly conserved in Klebsiella oxytoca and have been evolving in the host for more than 100 million years. Similarly, analysis of metagenomic clones obtained from 10,000-year-old ocean samples has revealed that the diversity of β-lactamases is mostly associated with ancient evolution.

Commencement of the antibiotic era

The beginning of the modern antibiotic era can be marked by the discovery of a synthetic prodrug salvarsan and neosalvarsan by Paul Ehrlich in 1910 to treat Treponema pallidum, a spirochaete bacterium that causes the sexually transmitted disease syphilis. Inspired by his own discovery of dyes that specifically stain bacterial cells, Paul Ehrlich started screening a panel of synthetic drugs and subsequently identified salvarsan.

Later on, salvarsan was gradually replaced by a sulfonamide prodrug prontosil, which was discovered by bacteriologist Gerhard Domagk. Although sulfonamides are still in clinical use as broad-spectrum antibiotics, large-scale use of these drugs was gradually replaced by the discovery of penicillin by Alexander Fleming in 1928. Fleming isolated and purified penicillin from a fungus Penicillium notatum that had accidentally contaminated a culture plate of Staphylococcus bacteria.

Later on, the large-scale purification of penicillin was conducted by a team of Oxford scientists (Howard Florey, Ernst Chain, and Norman Heatley), which helped penicillin mass production and distribution in 1945. In the same year, Alexander Fleming together with Howard Florey and Ernst Chain received the Nobel Prize in medicine "for the discovery of penicillin and its curative effect in various infectious diseases."   

First clinical use of antibiotics

Pyocyanase, an extract of Pseudomonas aeruginosa, was the first antibiotic that was used in a hospital to treat hundreds of patients in the 1890s. Pyocyanase, discovered by Emmerich and Löw, was found to be effective against a variety of pathogens and was in use until the 1910s. Although initially considered an enzyme, pyocyanase could be a combination of pyocyanin, quorum-sensing phenazine, and 2-alkyl-4-hydroxy-quinolones.

Appropriate Use of Antibiotics

The golden age of antibiotic discovery

The systemic evaluation of microbes and their ability to produce anti-microbial compounds was first initiated by Selman Waksman in the 1930s. He defined an antibiotic as “a compound made by a microbe to destroy other microbes” and discovered multiple antibiotics from soil-dwelling filamentous actinomycetes, including neomycin and streptomycin (antibiotics against tuberculosis).

The period between the 1940s and 1960s was considered the golden age of antibiotic discovery. The majority of antibiotics discovered during this period are still in clinical use today. However, a marked decline in their efficacy has been observed over time because of antibiotic resistance.

An abrupt decline in the rate of antibiotic discovery after the 1970s together with excessive use of existing antibiotics is the primary cause of antibiotic resistance. A few antibiotics that are currently under investigation are synthetic antibiotics or the derivatives of known classes of antibiotics. This calls for an urgent need of discovering new classes of antibiotics to treat multidrug-resistant bacterial infections.

Developments in antibiotic discovery  

New classes of antibiotics are primarily identified through large-scale screening of antibiotic-producing soil organisms. The path of antibiotic discovery has been rejuvenated by the identification of novel organisms from under-explored environments. In addition, the development of new techniques for genome mining and heterologous pathway expression has accelerated the discovery of new antibiotics.

The actinomycete genus Salinospora isolated from the marine environment has been identified as a good source of structurally novel antibiotics including salinosporamide A, which is currently under phase III clinical trial for the treatment of glioblastoma.

References

• Hutchings, MI. (2019). Antibiotics: past, present and future. Current Opinion in Microbiology. https://www.sciencedirect.com/science/article/pii/S1369527419300190
• Aminov RI. (2010). A Brief History of the Antibiotic Era: Lessons Learned and Challenges for the Future. Frontiers in Microbiology. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109405/
• The history of antibiotics. Microbiology Society. Available at: https://microbiologysociety.org/members-outreach-resources/outreach-resources/antibiotics-unearthed/antibiotics-and-antibiotic-resistance/the-history-of-antibiotics.html

Further Reading

• All Antibiotic Content
• Does What You Eat Affect Antibiotic Effectiveness?
• Does Long-Term Antibiotic Use Affect Bone Mass?
• The Effect of Antibiotics on the Gut Microbiome

Written by

Dr. Sanchari Sinha Dutta

Dr. Sanchari Sinha Dutta is a science communicator who believes in spreading the power of science in every corner of the world. She has a Bachelor of Science (B.Sc.) degree and a Master's of Science (M.Sc.) in biology and human physiology. Following her Master's degree, Sanchari went on to study a Ph.D. in human physiology. She has authored more than 10 original research articles, all of which have been published in world renowned international journals.