The serendipitous discovery of penicillin by Alexander Fleming in 1929 positively transformed modern medicine. Fleming’s decision to spend his summer holiday in East Anglia and his casual approach to laboratory housekeeping was an auspicious combination. After his return to the laboratory he observed that an uncovered culture plate of Staphyloccocus bacteria had been contaminated with a fungus Penicillium notatum. Fleming’s decision not to discard this plate but to study the phenomenon further was the start of a new era of modern medicine.
The therapeutic potential of penicillin to successfully treat infections that had previously killed patients was soon apparent. In 1941 the microbiologist Selman Waksman (who subsequently went on to discover more than 20 antibiotics himself) used the term ‘antibiotic’ for the first time. Antibiotics are small molecules that inhibit the growth of microbes and can be used clinically to treat a plethora of bacterial and fungal infections. The Golden Age of drug discovery had arrived and from the 1940s to the 1960s new drugs were discovered and developed. But as early as December 1945 Fleming’s sounded a note of warning in his Nobel Prize acceptance speech:
“It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them […]. The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant.”
Unfortunately, Fleming’ premonition has been uncannily accurate. Over the last 80 years or so we have seen bacterial pathogens develop resistance to almost all of the antibiotics we have in current, clinical use. Bacteria carry the information required for antibiotic resistance in their DNA and some bacterial species are resistant to certain antibiotics as a direct result of their genetic make-up, metabolism and cellular structure. Other bacteria develop resistance to antibiotics in two different ways. Firstly in large populations of bacterial cells, spontaneous mutation in bacterial DNA can cause an individual bacterium to develop a resistance to an antibiotic. Secondly, bacteria can acquire antibiotic resistance from DNA that is transferred from a resistant bacterium to a non-resistant one. This horizontal transmission of antibiotic resistance can even occur between different species of bacteria. However acquiring antibiotic resistance is not an evolutionary advantage for a bacterium until a selection pressure is applied: the antibiotic. The antibiotic destroys any bacteria that are sensitive to antibiotics (not resistant) but bacteria that have acquired antibiotic resistance survive and multiply ensuring that the antibiotic resistant bacteria become the majority within the bacterial population. The animation below gives a visual explanation of horizontal transmission of antibiotic resistance.
Antibiotics and antibiotic resistance are not modern phenomena. Scientists analysed ‘rigorously authenticated ancient bacterial DNA’ recovered from Late Pleistocene permafrost sediments located at a site in the Yukon, Alaska. They identified a plethora of genes encoding resistance to a variety of antibiotics used today. These results revealed that genes encoding antibiotic resistance are found in bacteria from environments that predated humans and our use of antibiotics. Antibiotic resistance has been around for a long time.
Society’s generous adoption of antibiotics as a force for good is understandable and represents the optimistic, utopian view that science will always have the answers. However our reliance on antibiotics has consequences for antibiotic resistance; it is speeding up the process. The more we use antibiotics the more resistant bacteria are becoming. It is less than a hundred years since Fleming ‘discovered’ penicillin and our reliance on antibiotics to treat life-threatening infections and prevent post surgery infections is at grave risk if we continue to use them inappropriately and with such casual abandon. Antibiotic use in modern agricultural practice and animal husbandry has increased dramatically and an increase in antimicrobial resistance has followed. Antibiotics are not effective against viruses yet antibiotics continue to be prescribed for viral infections and in some countries it is easy to purchase antibiotics without a prescription.
As patients, we continue to misuse antibiotics by demanding them for viral infections, and failing to finish the course of antibiotics when we feel better. The days when bacteria carried resistance to only one or two clinical antibiotics are becoming a thing of the past. Nowadays, it is not uncommon for life-threatening infections such as tuberculosis and gonorrhea to be caused by bacteria with extensive antibiotic drug resistance or even pan-drug resistance making them almost untreatable. Unfortunately, antibiotic resistance knows no borders. Cheap, easy travel means that resistant strains of bacteria can travel the globe effectively.
Unfortunately the Golden Age of antibiotic discovery is long gone; most commonly found antibiotics have been discovered and the discovery of a novel antimicrobial with a clinical impact is rare. In addition, pharmaceutical companies are reluctant to invest in a drug that is at best prescribed for a short period of time, and at worst kept on a shelf as a ‘reserve antibiotic’ to be used only when no other treatment is available.
Effective education, communication, and engagement lie at the heart of any solution and the good news is that this approach is working. Currently it is not just the medical profession and scientists who are highlighting this issue; society, the media, governments, and policymakers from across the globe now understand the scale of the problem. The result is that resources are being invested in examining the challenges and presenting potential solutions to this crisis and financial and regulatory incentives are being provided to address the lack of new antibiotics that are coming on stream. Concerted efforts are also being made across the agricultural and healthcare industries to improve antibiotic stewardship so that we preserve the usefulness of the antibiotics that we currently have at our disposal. Finally a priority must be to invest effort, expertise, and commitment to create a better-informed public that understands the issue of AMR and feels empowered to be part of the global solution.