A collective of chemists, biologists, and microbiologists spearheaded by scholars in Arts & Sciences at Washington University in St. Louis has discovered a method to modify an antimalarial medication and transform it into a strong antibiotic, part of a venture that has been over two decades in the making. Significantly, the newly developed antibiotic is anticipated to be largely resistant to the strategies that bacteria have developed to evade other medications.
“Antibiotic resistance is among the most significant challenges in healthcare,” stated Timothy Wencewicz, an associate professor of chemistry in Arts & Sciences. “This is merely one step on a lengthy path toward a new medication, but we have demonstrated that our idea is viable.”
The principal author of the investigation, John Georgiades, AB ’24, is currently a graduate student at Princeton University, having assumed control of the project while he was an undergraduate in Wencewicz’s laboratory. Additional co-authors comprise Joseph Jez, the Spencer T. Olin Professor in Biology; Christina Stallings, a professor of molecular microbiology at the School of Medicine; and Bruce Hathaway, a professor emeritus at Southeast Missouri State University. The results were published in ACS Infectious Diseases, a publication of the American Chemical Society.
A fresh strategy for antibiotics is urgently required because many frequently used medications are losing their effectiveness, Wencewicz noted. He highlighted Bactrim, a combination of sulfamethoxazole and trimethoprim. Commonly prescribed for treating ear infections and urinary tract infections, Bactrim impedes a bacterium’s capacity to synthesize folate, a vital nutrient for rapidly proliferating germs. “It has been prescribed so frequently that resistance has become very prevalent,” Wencewicz remarked. “For quite some time, there has been contemplation regarding what will take Bactrim’s place and what our next steps will be.”
Rather than fabricating new antibiotics from scratch, Georgiades, Wencewicz, and their associates utilized chemistry to modify cycloguanil, a drug already employed in the treatment of malaria. “It’s an ingenious way to rejuvenate a medication that is already approved by the FDA,” Wencewicz stated. Similar to Bactrim, cycloguanil functions by inhibiting the enzymes that organisms require to synthesize folate. It has rescued millions from malaria throughout the years, yet it was ineffective against bacteria due to its inability to penetrate the membrane surrounding bacterial cells.
Following numerous experiments, researchers succeeded in attaching various chemical keys to cycloguanil that unlocked access to the bacterial membrane. Once the new compounds infiltrated the cell’s inner workings, they launched a dual attack on the enzymes necessary for bacteria to produce folate. “Dual-action antibiotics generally prove to be significantly more effective than drugs that adopt a singular approach,” Wencewicz explained. While bacteria may manage to develop resistance to one element of the assault, they are unlikely to discover a method to thwart both simultaneously, he elaborated.
The novel compound demonstrated effectiveness against a broad spectrum of bacteria, including Escherichia coli and Staphylococcus aureus, two of the principal causes of bacterial infections. Unlike Bactrim and other current drugs targeting folate, some of the new compounds also exhibited potency against Pseudomonas aeruginosa, a pathogen that frequently infects individuals with compromised immune systems.
Despite several compounds showing potential in the laboratory, Wencewicz recognized the necessity to delve deeper into understanding the mission’s complexities. “We needed to grasp how these compounds were functioning on a molecular level,” he said. “That’s where John Georgiades stepped in.”
Georgiades, a Beckman Scholar and a Goldwater Scholar during his tenure at WashU, collaborated with Jez to employ X-ray crystallography in determining the structures of the chemical keys — a critical phase in comprehending their antibacterial capabilities. “We selected a few compounds with the highest potential and thoroughly analyzed their mechanisms,” Georgiades remarked.
Georgiades also partnered with Stallings to demonstrate that the new compound was effective against Mycobacterium abscessus, a particularly challenging organism that can lead to lung infections and other ailments in those with cystic fibrosis. “The collaborative environment at WashU enabled this project to come to fruition,” Georgiades stated. “Over 20 individuals contributed to this paper from various institutions, each playing a significant role.”
The involvement of Wencewicz in this project dates back to his undergraduate days at Southeast Missouri State University. It was there that he first met Hathaway, a chemist who had been experimenting with antibiotic compounds since his own postdoctoral research in the early 1980s. Hathaway, who is now a professor emeritus of chemistry at SEMO, provided the groundwork for this antibiotic advancement.
“This work pioneers new avenues based on efforts that began at the outset of my professional journey,” Hathaway remarked. “Since my retirement, in certain aspects, this stands as my crowning achievement. I am extremely thankful to Tim and everyone who recognized the potential of this research direction and elevated it to the next stage.”
The partnership between Wencewicz and Hathaway traversed several institutions and spanned nearly twenty years. They were eager to discover the right chemical keys to assist existing medications in penetrating bacterial membranes. Ultimately, Wencewicz accumulated a repertoire of candidate compounds which he carried with him as his career progressed through the University of Notre Dame, Harvard, and eventually WashU.
“Antibiotics once formed the backbone of the pharmaceutical sector, but now they have become somewhat of an abandoned category of medications,” Wencewicz observed. “As researchers, we can step in, embrace the risks, and cultivate the knowledge foundation that will lead to transformative advancements.”
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