The coming post-antibiotic era

Today, the challenge for science is to keep pace with the emergence of new bacterial strains that are resistant to available antibiotics. At a hospital in Nevada, US, in August 2016, a 70-year-old woman died of a bacterial infection that was resistant to 26 antibiotics.

The antibiotic era was born with the discovery of Penicillin 90 years ago on September 28, 1928, which revolutionised the management of bacterial infections. This emergence can be attributed probably to the first antibiotic to be used to treat human infections developed by Rudolf Emmerich and Oscar Low in the early 20th century. Emmerich and Low discovered that the green bacteria isolated from injured patients’ bandages inhibited the growth of other microbes. While Penicillin and other antibiotics marked the onset of the antibiotic era, we may now be moving towards a post-antibiotic age.

Antibiotics are molecules that kill or stop the growth of micro-organisms, which include both bacteria and fungi. Most classes of antibiotics, including the Beta-lactam antibiotics, tetracyclines and aminoglycosides are originally derived from natural sources and further chemically modified to confer better properties on the drug. However, some important classes of antibiotics such as sulfa antibiotics, the quinolones, and the oxazolidinones are man-made, and originate totally from synthetic chemical operations.

In 1896, the French medical student Ernest Duchesne originally discovered the antibiotic properties of Penicillium but failed to report a connection between the fungus and a substance with anti-bacterial properties, and Penicillium was forgotten by the scientific community until Alexander Fleming’s rediscovery of it.

Louis Pasteur and Robert Koch pioneered research in the 19th century to study bacteriology and its linkage with infectious diseases. Pasteur showed that some micro-organisms contaminated fermenting beverages and concluded that micro-organisms infected animals and humans. Koch discovered Bacillus anthracis, Mycobacterium tuberculosis, Vibrio cholerae.

Also, the anti-bacterial effects of some dyes that the modern era of anti-microbial chemotherapy uses began when Paul Ehrlich noted that some stains were toxic for bacteria, though they are not antibiotics, and started searching for the ‘magic bullet’ that selectively targeted a disease-causing organism while having no negative effect on human tissues. He synthesised and screened hundreds of compounds to eventually discover and develop the first modern chemotherapeutic agent, Salvarsan, in 1909 for the treatment of syphilis caused by Treponemapallidum. With further discovery of diphtheria anti-toxin by Ehrlich, anti-toxins then became the basis of anti-bacterial therapy.

Fleming received the Nobel Prize in Medicine 1945 for his discovery of Penicillin as the first natural antibiotic in 1928. In the pre-antibiotic era, anyone with a bacterial or fungal infection suffered severely or even died due to its adverse effects. However, some people survived deadly bacterial infections due to the innate immune response systems, but mortality rates were much higher than before the discovery of antibiotics.

During World War I, 1914-18, which coincided with the pre-antibiotic era at Gallipoli, 5,482 soldiers were killed in action, of whom 2,012 succumbed to their wounds due to bacterial sepsis. Thereafter, Gerhard Domagk discovered and developed sulfonamides (Prontosil), the first drugs effective against bacterial infections. Domagk treated his own daughter with Prontosil to fight a severe streptococcal infection and eventually saved her life. They had a central role in preventing infections during World War II. With the rising use of these antibiotics during World War II, deaths from infection versus combat deaths were one-to-nine for US soldiers.

In 1944, Dorothy Hodgkin crystallised Penicillin and determined its structure by X-ray crystallography to resolve the controversy around the chemical constitution of the antibiotic and pave the way for the discovery of improved antibiotics by modification of the natural products and adopting totally synthetic approaches.

Later in 1944, Selman Waksman, working at Rutgers University, systematically screened soil bacteria and fungi as sources of antibiotics and discovered a number of new antibiotics, including streptomycin, actinomycin, clavacin, streptothricin, grisein, neomycin, fradicin, candicidin, candidin and others. Waksman received the Nobel Prize in Medicine in 1952 for discovery of streptomycin, the first antibiotic effective against TB.

Today, extra efforts are needed to conserve our existing antibiotics, besides structural modifications and to also develop new molecules to combat newer bacterial strains. Many molecules have to be tested for any strain before identification of a potential agent. Research into novel bacterial targets linked to whole genome sequencing may eventually make this work easier, but in the meantime, natural habitats where these microorganisms are found are being eroded by deforestation and global warming. Mankind has to come to terms with the reality of the post-antibiotic era.

(The writer is Assistant Professor, Department of Life Sciences, Christ Deemed to be University, Bengaluru)