The Antibiotic Discovery Pipeline: Will It Run Dry?
On September 28, 1928, Alexander Fleming discovered penicillin—the world’s first “wonder drug.” Antibiotics are defined in the Merriam Webster dictionary as “drugs that are used to kill harmful bacteria and to cure infections.” At the time of penicillin’s discovery, other antibiotics were in use, but none were as spectacularly life-saving as penicillin proved to be.
The story of Fleming’s serendipitous observation of a mold, Penicillium notatum, on a petri dish producing a substance that killed Staphylococcus aureus is the subject of many articles and books. The contributions of the Oxford professors Howard Florey and Ernst Chain, who shared the Nobel Prize for Physiology or Medicine with Fleming in 1945, are equally amazing.
But in his acceptance speech of the Nobel Prize, Fleming forecast the emergence of resistance of bacteria to penicillin if it wasn’t used properly. Sure enough penicillin resistance was recognized soon after its introduction in practice, and now, some 91 years after his discovery, the “wonder” drug status of antibiotics has shifted from “astonishment at something awesomely new” to “a feeling of doubt or uncertainty.”
The phenomenon of antibiotic resistance is rooted in the evolutionary biology of bacteria. Ever since they appeared on Earth about 3.8 billion years ago, bacteria have been fighting for survival. Their “survival of the fittest” lifestyle included the development of genetically-mediated mechanisms to kill competitors. One very successful strategy was the production of substances that are lethal to other microbes, such as antibiotics. While fungi like Penicillium didn’t appear at the beginning of life, they too produce antibiotics, such as penicillin, that ward off bacteria. Several billion years later, we’ve co-opted their products for our medicinal purposes.
So how serious a problem is antibiotic resistance? In 2013, Dame Sally Davies, Britain’s Chief Medical Officer, predicted that within two decades antibiotic resistance could cause tens of millions of patients to die following even minor surgery. She also said that the problem is growing so large, and so serious, that the British government should rank it alongside terrorism and climate change as one of the country’s biggest threats. One year later, in 2014 the World Health Organization provided evidence that antibiotic resistance is found in every region of the world. They suggested we have entered a “post-antibiotic era” in which people are dying from simple infections that had been completely treatable for decades. And many infectious diseases specialists, myself included, consider antibiotic resistance to be the single biggest infectious disease threat that we are currently facing.
Following the introduction of penicillin for clinical use in 1942, well over 100 other antibiotics were released into the pharmaceutical market. Some of these agents belong to the same class of antibiotics as penicillin, such as amoxicillin, but most are other types of antibiotics, for example, cephalosporins (like Keflex), macrolides (like erythromycin), and fluoroquinolones (like ciprofloxacin). In fact, in the early years of my practice as an infectious diseases specialist in the 1970s and 1980s, new antibiotics were being released at a pace that was impossible for non-specialists to stay on top of.
So, why were so many new antibiotics being developed? And why did the flood turn into a trickle at the turn of the century? The answer to the first question is easy: bacteria were busy doing their own thing in response to antibiotics; developing resistance. Fortunately, the pharmaceutical industry was doing a wonderful job keeping up with them. The answer to the second question, however, is more complicated, but in part was due to the diminishing profits from antibiotics, drugs usually taken for only a few days or weeks compared to “blockbuster drugs,” like Lipitor and Zoloft, that are taken for life.
Bacteria are very clever. They possess three different strategies to resist the effects of antibiotics. First is the production of enzymes that destroy antibiotics, for example, a penicillinase that inactivates penicillin. Second is the alteration of the antibiotic target so that it can no longer bind to the bacterium. The third is the use of an efflux pump that drains the antibiotic from the bacterial cell before the antibiotic comes into full effect. Importantly, bacteria develop these resistance mechanisms by mutating existing genes, or by acquiring new genes from other strains or species, including viruses.
Sadly, the antibiotic discovery pipeline began to slow just when we needed new antibiotics most—at the time that superbugs were emerging. (The term superbug was coined by the media to describe bacteria that are resistant to multiple antibiotics.) The first of the superbugs to grab attention was methicillin-resistant Staphylococcus aureus (MRSA), which got its start by causing infections in hospitalized patients in the 1970s and then moved into the community toward the end of the 20th century. Shortly thereafter, vancomycin-resistant enterococci (VRE) appeared. These bacteria are classified as “gram-positive” based on their appearance under the microscope after a staining procedure.
To their credit, pharmaceutical companies developed alternative antibiotics that were effective against gram-positive superbugs. However, the emergence of gram-negative superbugs in the 21st century posed an even greater challenge. Some of these superbugs are resistant to all available antibiotics, and patients succumb to their infections. (Anecdotal cases have been reported of such patients on death’s door-step that were treated successfully with viruses that kill bacteria called bacteriophages.)
Good news, however, is to be found in a July 2019 report from the Infectious Diseases Society of America that the number of new antibiotics annually approved for marketing in the U.S. has reversed its previous decline, likely influenced by new financial incentives and increased regulatory flexibility for pharmaceutical companies. And in June 2019, approximately 42 new antibiotics with the potential to treat serious bacterial infections were reported to be in clinical development.
But you might ask, “What can be done in the meantime to slow future emergence of antibiotic resistance?” The answer to this question is tied to improved oversight of the two major groups of professionals who are flooding the environment with unneeded antibiotics, thereby encouraging development of antibiotic resistance: 1) physicians who prescribe antibiotics for viral infections (such as, the common cold, acute bronchitis, and sinusitis), and 2) farmers who use antibiotics in animal feed to fatten them up for market. Here, however, there is also good news. Antibiotic stewardship teams, mentioned in the previous Germ Gems blog, have become standard in most hospitals in the U.S., and early evidence indicates they are helping reduce the use of unneeded antibiotics. And, as you likely have noticed, many purveyors of poultry and other foods are promoting “antibiotic-free” products.