By George Tatoris
In 1904, German researcher Paul Ehrlich decided the world needed a new cure for syphilis. At the time, the common treatment was both ineffective and often produced harmful side effects. Ehrlich believed a better drug could be made that would only target the disease-causing pathogens and not the patients.
He called these hypothetical compounds “magic bullets.” We call them antibiotics.
After testing hundreds of new compounds, the 606th compound yielded results, becoming the first chemical drug — Salvarsan — but it was far from magic. The discovery paved the way for Alexander Fleming to discover penicillin in 1928. Over the next few decades, more antibiotics were discovered using a similar process to Ehrlich.
By this time, the scientific world believed antibiotics had won them the battle against bacterial infections, however, these magic bullets were not as flawless as people believed. After use of antibiotics became widespread, pathogens adapted and antibiotics lost its magic.
Antibiotic resistance was the topic of the biology department’s first Colloquium seminar this semester. Alita Miller, head of biology at Entasis Therapeutics, a subsidiary of AstraZeneca that focuses on the early stages of drug development, spoke to students and faculty about her research on Friday, Jan. 27, in room 101 of the Physics Building.
“All of the seminars function to enrich the intellectual community within the departments and school,” said Keith Pecor, an associate professor of biology and chair of the department.
Miller graduated from Kalamazoo College with a Bachelor of Arts in biology and earned her Ph.D in biochemistry and molecular biology from the University of Chicago.
Students and faculty from the biology, chemistry and nursing departments packed the lecture hall wall to wall — some had to sit on the stairs.
“It was fantastic to see so many of our students take advantage of this opportunity to hear about cutting-edge applied research in biology and chemistry,” said Kathryn Elliott, an assistant professor of biology.
Armed with a slide show, Miller began the seminar explaining all of the good accomplished by antibiotics — the treatment of cancer, heart surgery and care for premature infants, among other things, were all made possible thanks to antibiotics.
The mood at the time was that of optimism. Miller demonstrated this with a photo of a surfer riding the crest of a massive wave. Like the surfer who had conquered the wave, science had conquered bacterial infections. Antibiotics gave humanity power over once-deadly diseases.
However, “in that power hung the seeds of crisis,” Miller said.
Resistance to antibiotics appeared soon after its discovery. Antibiotics act as a “selective pressure” on pathogens, Miller said, meaning they make certain traits more desirable for reproduction.
When an antibiotic is used to fight infection, it only kills those organisms that do not have the genetic traits to resist the drug. Those that do survive and go on to reproduce more bacteria with the ability to resist the antibiotic.
Over the next few decades, each new drug lost its efficiency one-by-one. Miller demonstrated this with a timeline marking when an antibiotic was discovered, when resistance was first identified and when the drug lost its efficacy. After a heap of antibiotic-resistant pathogens sprung up in the ’80s and ’90s, scientists began forewarning of a post-antibiotic future. Things seemed grim.
“This is where we are today,” Miller said, switching to another slide of a surfer, this one tumbling into the wave he was trying to ride. The crowd laughed.
The first antibiotic Miller helped discover kills drug-resistant Neisseria gonorrhoeae (N. Gonorrhoeae), which causes gonorrhea and is considered one of three “urgent threats” by the Centers for Disease Control and Prevention. While infections are low in the United States, the speed at which these resistant strains can spread makes N. gonorrhoeae an immediate threat.
It took the small team of Entasis just six months to discover the antibiotic QPT-1. It was used to create the drug Zoliflodacin, which is currently in clinical trials.
“The rise of drug-resistant gonorrhea is alarming, and while this bacterium is not usually fatal, untreated infections can cause chronic pain and infertility,” Elliott said. “So, it was exciting to hear that a promising new drug is in clinical trials.”
For many companies, it isn’t profitable to find a new way to kill a bacterium. Most modern antibiotics are improvements on old ones or are only designed to attack a specific component of bacteria, not kill them.
Entasis went against this trend with QPT-1, screening thousands of compounds to find a new way to kill. They concerned themselves only with the compound’s ability to kill — they didn’t question the results, they only cared if the compound did its job, saving money and time. The new drug is effective because N. gonorrhoeae never experienced the drug’s unique method of attack before, so it has no defenses for it.
Miller mentioned two genes that lead to antibiotic resistance in her seminar — New Delhi metallo-beta-lactamase 1 (NDM-1) and mobilized colistin resistance (MCR-1). Both can be spread to other bacteria through horizontal gene transfer, when genetic material is transferred in ways other than from parent to offspring.
NDM-1 is a beta-lactamase, an enzyme that “chews up” beta-lactam antibiotics like penicillin, Miller said. MCR-1, discovered in 2015 in a string of E. coli, allows bacteria to resist colistin, an antibiotic used only when a disease has resisted every other drug administered against it.
Miller and Entasis are working on a drug that can fight against multidrug resistant acinetobacter — a “serious threat,” according to the CDC, one tier below urgent — currently known as ETX2514.
The task of finding this drug was complicated by multiple beta-lactamase enzymes within bacteria working together to fight off the effects of the drug. With so many different combinations of enzymes, Entasis could only find drugs that would be effective against some, but not all.
After a lot of testing, Entasis discovered ETX2514, which, when used in tandem with the drug Sulbactam, stopped all beta-lactamase combinations with the least amount of concentration and dosage.
Elliott hoped students walked away understanding the gravity of antibiotic resistance and how public policy can speed or hamper progress on a new drug.
“This is one case where the scary stories in the media are not always an exaggeration,” Elliott said. “The post-antibiotic era is right around the corner unless we do something to prevent it.”
Pecor hoped biology students learned about the flexibility of their degree.
“At open houses and during advising sessions, a common question is, ‘What can I do with a biology degree if I don’t want to be a doctor?’” Pecor said. “Our seminars help answer that question by showcasing the people doing many of those jobs.”
During a question and answer session, Miller stressed that, although these drugs might end up becoming obsolete in the future — “We’ll be lucky if they work in 10 to 20 years,” she said, it is still important to continue making these drugs.