Resurgence of Old Bacterial Infections and New Research to Curb Them
Considered the quintessential medical revolution of the 20th century, antibiotics turned deadly bacterial infections into curable diseases and transformed medicine and surgery. Yet, 80 years after the discovery of penicillin — which saved millions of lives — antibiotics as we know them are not the cheap and effective “wonder drugs” they used to be, due to emergence of antibiotic or antimicrobial resistance (AMR). Some diseases that we considered long gone or easy to treat are coming back from the past returning as serious public health threats.
A 2014 Global Health Organization surveillance report stated we have entered the “post-antibiotic era,” in which common infections and minor injuries can kill again and the success of surgery, organ transplantations and cancer chemotherapy could be compromised.
AMR: How It Happens and How It Spreads
Antibiotics kill bacteria by disrupting functions that are essential for their survival. AMR arises when bacteria develop the ability to defeat antibiotics that were once able to kill them. Just like any living organisms, bacteria evolve over time and some acquire resistance to stressful conditions in their environment, including antimicrobial drugs. Bacteria that naturally evade the host immune system have a further survival advantage and are more likely to develop AMR faster. They rapidly outnumber the wild type bacteria. Additionally, genes that confer drug resistance can transfer from one species of bacteria to another and rapidly spread.
While evolution is natural, human behavior has amplified bacterial resistance to antibiotics. Antibiotic use creates a selective pressure for resistant organisms, as sensitive ones are killed and those that survive have less competition in the environment. Therefore, AMR is enhanced by excessive or inappropriate use of antibiotics, such as:
- Patients self-medicating with antibiotics to treat conditions that are not caused by bacteria (for example the flu or other viral infections);
- Healthcare providers overprescribing antibiotics “just-in-case” or prescribing broad-spectrum drugs instead of more specific ones;
- Excessive agricultural use that causes transfer of resistant bacteria from farm animals to people and affects the good bacteria present in the environment.
The AMR crisis is worsened by the lack of new antibiotic development by the pharmaceutical industry — in the decade between 2000 and 2010 only five new antibiotics have been approved for clinical use and AMR bacteria have emerged against these new antibiotics as well1.
Several strains of resistant bacteria have been isolated so far, such as drug-resistant Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumanii, Enterobacteriaceae, Gonococcus and methicillin-resistant Staphylococcus aureus (MRSA). Strains of Mycobacterium tuberculosis have become resistant to 10 to 20 antibiotics used in different regimens to treat them and MRSA has now developed resistance to vancomycin, an antibiotic specifically used to treat MRSA.
“We face a very pressing situation,” said Farokh Dotiwala, M.B.B.S., Ph.D., assistant professor in Wistar’s Vaccine & Immunotherapy Center. “A U.K. public health study predicts that by 2050, 10 million people will die every year because of antibiotic-resistant infections, such as gram-negative bacteria, tuberculosis and malaria2. The cost associated with AMR will run into 80 trillion dollars per year.”
AMR infections frequently occur in hospitals. The Centers for Disease Control estimated that they account for approximately 1.7 million infections and 99,000 deaths each year in the U.S. alone.
AMR represents an important economic burden to the health care system and to patients. When first-line and then second-line antibiotic treatments fail, doctors have to use more expensive drugs that have more side effects, while patients with resistant infections tend to require longer hospital stays. In 2006, hospital-acquired sepsis and pneumonia cost the U.S. health care system more than $8 billion.
In response to the worsening antibiotic resistance crisis, the pharmaceutical industry has begun to revamp its antibiotic discovery and development programs and the number of new molecules in the pipeline has been on the rise since 2014.3
Wistar is Contributing Important Research for the Development of Novel Antimicrobial Strategies
Dotiwala and his lab are developing a novel antibiotic strategy to combat AMR. This approach targets an essential pathway in bacteria, called isoprenoid synthesis pathway, and activates killer immune cells at the site of infection in order to destroy the bacteria that acquire resistance to antibiotics. Using computer-aided molecular modeling, the Dotiwala lab has evaluated millions of commercially available compounds for their ability to specifically target the isoprenoid synthesis pathway. The best hits have been validated and further studied with the goal of finding select compounds to move forward to clinical trials.
The team is also taking an innovative approach to developing non-traditional antibiotics by “copying” natural antibacterial molecules used by our immune system.
During his postdoctoral training, Dotiwala discovered a process that was named microptosis, through which killer immune cells — T lymphocytes and natural killer (NK) cells, attack and kill intracellular bacteria and parasites during an infection.
Intracellular parasites grow and reproduce inside the cells of a host. As a defense mechanism, T cells and NK cells destroy infected cells by poking holes in their membranes and delivering toxic proteins that break down the cellular structures. What Dotiwala found is that killer cells can also use a similar mechanism to kill microbes themselves.
At Wistar, the Dotiwala lab is further studying proteins used by killer immune cells in this process, with the goal of repurposing these substances as novel therapies for drug-resistant bacterial infections.
“Such an approach is expected to be very specific and not cause major side effects, because we would be using weapons that are naturally part of our immune system’s arsenal to fight microbes,” said Dotiwala. “Importantly, due to simultaneous targeting of multiple essential bacterial systems by microptosis, the bacteria would not be able to develop resistance to this type of treatment, and this would be a critical advantage over traditional antibiotics.”
While this and other research to create new medicines against AMR bacteria come to fruition for patients, we need to make prudent use of the “old” classes of antibiotics that are still effective.
- Antibiotic resistance threats in the United States, 2013. April 2013. Centers for Disease Control and Prevention Office of Infectious Disease.
- Antimicrobial Resistance: Tackling a Crisis for the Health and Wealth of Nations. Dec. 2014. O’Neill J., Review on Antimicrobial Resistance.
- Targeting innovation in antibiotic drug discovery and development: The Need for a One Health—One Europe—One World Framework, 2016. Renwick M.J., Simpkin V. and Mossialos E. Appendix 1, page 83