A Fierce Fighter in the Battle Against Deadly Superbugs

An Old Problem in Need of a New Solution

According to the World Health Organization (WHO), antimicrobial resistance (AMR) is a major threat to global health. About 1.3 million deaths per year are attributable to antimicrobial-resistant bacteria. That’s more than the mortality rate of AIDS and malaria combined. For years, WHO has warned that “too few antibacterials are in the [developmental] pipeline.”

Scientists and pharmaceutical companies kept up with the emergence of resistance to new antibacterials until the mid-20th century, according to the article “A Brief History of Antimicrobial Resistance” in the American Medical Association’s Journal of Ethics. By using methods that derived new compounds from natural products and modifying them to meet clinical needs, the industry was able to stay ahead of AMR.

However, as antimicrobial product use increased in healthcare settings, so did resistance. In addition, antimicrobial applications in agriculture were discovered and encouraged. Due to overcrowding in livestock settings, antibiotics were used in animals to prevent illness and increase growth rates. This lowered the effectiveness of the medications, especially in organisms that crossed from animals to humans.

Another factor that created an environment in which resistant bacteria thrived was that pharmaceutical companies lacked a financial incentive to continue developing new antibiotics. As illness from infectious disease dropped, and rates of cancer and heart disease rose, the companies spent more money on research and development to treat those conditions.

Other Ways to Fight Superbugs

Although human misuse of antibiotics has contributed to AMR, superbugs are not entirely a human-made phenomenon. Bacteria, like most other organisms, evolve to survive, and bacterial resistance occurs naturally and has been occurring for more than 30,000 years. In addition, once bacteria have evolved resistance to antibiotics, they can share that genetic information with other bacteria through a process known as conjugation.

Scientists also study antibiotic persistence, another way bacteria evade elimination by antibiotics. Antibiotic persistence occurs when bacteria enter a dormant state after antibiotic treatment or when they are subjected to other stresses. The bacteria are not killed; they just stop growing.

“Resistance is the major problem,” said Nathalie Balaban, a biophysicist at the Hebrew University in Jerusalem. On the NPR podcast Short Wave, Balaban explained that persistent bacteria are those that remain in the body after antibiotic treatment. “In a healthy patient, it’s enough for the antibiotic to kill most of the bacteria or even to arrest the growth of the bacteria.” Their bodies will do the rest to purge the bacteria. But in immunocompromised people, dormant bacteria can start to grow again and even develop into a resistant strain that can infect others.

However, further lab studies of these persistent bacteria revealed that the dormant state is not organized. Bacteria forced into dormancy don’t have a regulated way to respond to their environment. Balaban said the bacterial membrane is more permeable in this chaotic state. One option to prevent the organism from re-emerging during a long infection is to also treat them with membrane-targeting compounds before antibiotic treatment is ended. This can more effectively eliminate the threat of bacterial resistance.

Another option to tackle superbugs is to develop targeted viruses, called phages, that infect bacteria but pose no threat to humans. Phages will find a bacterium and hijack it by latching on and injecting it with the phages’ genetic material. As a result, the bacteria become a phage incubator rather than an active infection agent. It will reproduce phages until the cell is so full that it explodes. Then the baby phages will go on to invade other bacteria, with the same result.

The tricky part of this method is that phages target only specific bacteria, so if a patient is infected with a superbug, the right phage must be identified to fight the infection.

The best option to fight AMR is still new antibiotics.

A Surprising Find

The discovery of the potent new antibiotic, methylenomycin C lactone, was reported in a recent paper in the Journal of the American Chemical Society. Chemists from the University of Warwick and Monash University in the U.K. uncovered the molecule hidden in plain sight in a familiar bacterium, Streptomyces coelicolor. S. coelicolor produces methylenomycin A, which has been synthesized many times since its discovery 50 years ago.

“No one appears to have tested the synthetic intermediates for antimicrobial activity,” Professor Greg Challis, co-lead author from the Department of Chemistry at the University of Warwick and the Biomedicine Discovery Institute at Monash University, explained. “By deleting biosynthetic genes, we discovered two previously unknown biosynthetic intermediates, both of which are much more potent antibiotics than methylenomycin A itself.”

S. coelicolor may have originally evolved to produce the stronger antibiotic, but over time shifted to producing the weaker version, according to co-lead author Dr. Lona Alkhalaf, Assistant Professor at the University of Warwick. She echoed Professor Challis’ observation about finding a new intermediate: “Finding a new antibiotic in such a familiar organism was a real surprise.”

Pre-methylenomycin C lactone appears to be effective against Staphylococcus aureus and Enterococcus faecium, the bacterial species responsible for Methicillin-resistant Staphylococcus aureus (MRSA) and Vancomycin-resistant Enterococcus (VRE), respectively. Given that vancomycin is often considered a last-resort antibiotic, a more potent alternative could significantly alter treatment strategies for resistant infections.