According to the CDC, antibiotics have been over-prescribed by doctors for the about the last decade. This is mostly due to the effective nature of antibiotics at treating bacterial infections, but natural selection has not allowed this imbalance to continue. As more antibiotics are taken to treat infections (or even taken inappropriately against viral infections), we are selecting for microbes resistant to such antibiotics, which will select for a new generation of drug-resistant pathogens, or “superbugs”. Current research has shown that antibiotic resistant bacteria are predicted to kill 10 million people by the year 2050. This is an obviously pressing issue, as our current treatments of infections with antibiotics will soon prove futile; the need for novel antibiotics has never been greater. Thankfully, a team led by Bradley Hover of Duke University Medical Center has had success with a “new” technique for discovering antibiotics.
Despite this current discussion on antibiotic overprescription, few people know what antibiotics really are or where they come from. Antibiotics, also referred to as natural products or NPs, are actually products of bacteria or fungi that can kill or inhibit the growth of other bacteria (2). They originally evolved as a way for certain bacteria to reduce competition with other neighboring bacteria. The most well known antibiotic was an accidental discovery by Alexander Fleming: after leaving open a dish of bacteria culture, Fleming returned to find mold growing on the plate and noticed that wherever the mold grew, the bacteria had died. Known today as penicillin (because it came from the mold species Penicillium notatum), it is used to treat a variety of ailments from scarlet fever to pneumonia. Although his work is the most cited example of an antibiotic, the majority of compounds we use today originally came from soil bacteria; this list includes streptomycin, chloramphenicol, and tetracycline. Despite being the pioneer of the modern antibiotic and confirming the success of the penicillin, Fleming foresaw the danger of its overuse as early as 1945: “public will demand [the drug and] … then will begin an era … of abuses” (3). Our only defense against these drug-resistant bugs is to find new types of antibiotics, and to continue the arms race against infectious bacteria.
Unfortunately, new discoveries of natural products have dropped significantly in recent years. This is most likely due to the fact that the bacteria used to search for these NPs have been in culture too long, and the only hits scientists have been getting are rediscoveries. This can be explained by the limited genetic diversity of bacteria in culture. Almost all bacteria get most of their diversity from sharing plasmids in a process called conjugation. If a culture of bacteria is studied for a while in the lab, there is only so much conjugation that can occur before all useful plasmids have been shared. Without the introduction of new bacterial strains, there will be no more conjugation and no new proteins to be discovered. Additionally, bacteria and fungi produce NPs as a way to eliminate competition, but if their environment is favorable and there is no need to compete, these proteins (which we use as antibiotics) will not be produced.
This is why many scientists have abandoned searching bacteria for their natural products and have moved on to synthesizing and testing new chemical compounds. Hover et al., however, have returned to the roots of antibiotic discovery, collecting 2,000 unique soil samples to screen for new antibiotics. Since it would be way too time consuming to culture the bacteria they found and then sequence their complete genomes found, the group took advantage of a technique called “metagenomics”, a process that allows scientists to sample DNA sequences from the environment without needing to know which organisms lived there (1). By choosing a known family of antibiotics (calcium-dependant antibiotics) as a reference point, they were able to screen all the bacteria in the soil for similar compounds. The beauty of this process is that it can be repeated for all known NP families, while the drawback is that novel families will be much more challenging, although not impossible, to find.
After scanning the genomes from all the collected bacteria, Hover et al. discovered a new class of antibiotics that are calcium-dependent: the malacidins. This class of natural products existed in some of the cultured bacteria that had been previously studied in laboratories, but had not been discovered due to the drawbacks of culture-dependant studies explained above. The discovery of this new antibiotic is exciting for the medical community because is has shown to be active against multidrug-resistant bacteria, and could be a new tool in our fight against the feared “superbug.” It also protected against a bacterial strain Staphylococcus aureus, more commonly known as a Staph infection, which used to be susceptible to methicillin, but has since evolved resistance.
Hover et al. are not the only ones with the idea of returning to soil bacteria for new NP’s. In 2010, Yale University started a program called “Small World Initiative.” The main idea of the program is to crowdsource soil sample collection, which saves scientists the time of going out into the field and allows participating members of undergraduate institutions to contribute to the advancement of microbiology. Following the example of “Small World Initiative,” the Microbiology Society in the UK initiated a program called “Antibiotics Unearthed” in 2015. The idea is similar: the general public is encouraged to go out and collect soil samples, carefully label the sample, and later track it as it is received and even used by scientific teams. These initiatives brilliantly combine community effort with the goal of scientific progress, and stimulate interest in the field of microbiology. Considering the impending need for new antibiotics against the predicted superbugs, these initiatives have come just in time.
- Hover, B. M., Kim, S., Katz, M., Charlop-Powers, Z., Owen, J. G., Ternei, M. A., Brady, S. F., et al. (2018). Culture-independent discovery of the malacidins as calcium-dependent antibiotics with activity against multidrug-resistant Gram-positive pathogens. Nature Microbiology, 3:415-422.
- “The History of Antibiotics.” Microbiology Society, 2018, microbiologysociety.org/education-outreach/antibiotics-unearthed/antibiotics-and-antibiotic-resistance/the-history-of-antibiotics.html.
- Ventola, C. L. (2015). The Antibiotic Resistance Crisis: Part 1: Causes and Threats. Pharmacy and Therapeutics, 40:277-283.