A fresh perspective may change how we utilize antibiotics. By targeting the pathogen’s specific and concealed metabolic ‘weaknesses,’ researchers are presenting a new resource in the global effort against antibiotic resistance and in the quest for similar combination therapies for other medical conditions.
Melioidosis, a bacterial infection leading to fever, pneumonia, and sepsis, poses two significant difficulties for infectious disease specialists: it has a mortality rate of about 50% among those infected, and it is extremely challenging to treat, even in nations with sophisticated healthcare systems.
Melioidosis is caused by a highly virulent bacterium that has even been utilized as a biological weapon in the World Wars. Treatment requires an expensive, protracted IV and antibiotic regimen, which is especially hard to implement in parts of Southeast Asia and northern Australia where melioidosis is common. While the disease is rare in the U.S., the first documented case of environmental transmission occurred here in 2022.
Seyedsayamdost Lab at Princeton Chemistry presents a hopeful treatment for this neglected tropical illness, using a combination of low-dose antibiotics designed to target the pathogen without harming the gut microbiome.
The approach developed by the researchers signals a potential change in antibiotic usage. By focusing on the pathogen’s specific and hidden metabolic “weak spots,” the lab is contributing to the global fight against antibiotic resistance and exploring similar combination therapies for various diseases.
“Typically, antibiotics are like nuclear weapons. They are broad-spectrum and are used in such high doses that they obliterate nearly everything around them, including beneficial bacteria. This is a significant issue,” explained Professor of Chemistry Mohammad Seyedsayamdost. “Our research found that even low doses of antibiotics reveal susceptibilities that are hard to identify but can be utilized once discovered. That was the moment of realization.”
“Using low or sub-inhibitory doses of antibiotics does not hinder the pathogen’s growth, but rather significantly influences its physiology and metabolism. Recognizing this allowed us to exploit this unique reaction to combat a challenging organism.”
The lab’s research, titled *Combatting melioidosis with chemical synthetic lethality*, has been published in the *Proceedings of the National Academy of Sciences* (PNAS), in collaboration with the Davis Lab at Emory University and the Chandler Lab at the University of Kansas.
“What excites me most about this paper is its potential to reshape our perspective on antibiotic development,” said Yifan Zhang, the paper’s lead author and a former graduate student at the Mo Lab. “There has been a growing global challenge with antimicrobial resistance for a considerable time, yet the development of new antibiotics has been unacceptably slow. With our study, we aimed for a fresh approach that doesn’t solely concentrate on discovering a new ‘magic bullet’ but instead seeks to outsmart pathogens by exploiting their metabolic weaknesses.”
“This work underscores the importance of thinking beyond conventional boundaries in science,” Zhang emphasized, now a medical student at Robert Wood Johnson. “Integrating concepts from oncology with our understanding of microbiology and microbial metabolism challenged many assumptions regarding how antibiotics are expected to function. Witnessing those risks result in a discovery that could genuinely assist patients is thrilling.”
Examining the pathogen using HiTES
Melioidosis is caused by the bacterium *Burkholderia pseudomallei*. Traditionally, antibiotic effectiveness against this organism is gauged by observing *Burkholderia* growth visually or with a simple assay before treating it with a broad-spectrum antibiotic, effectively using antibiotics as blunt instruments.
However, the Mo Lab employed an alternative method called High Throughput Elicitor Screening (HiTES), a technology for which Seyedsayamdost received a MacArthur Prize in 2020, enabling a deeper exploration of the metabolome for indicators of bacterial vulnerability.
HiTES demonstrated that the pathogen’s metabolism undergoes significant changes when exposed to low-dose antibiotics. Importantly, low-dose trimethoprim triggers a secondary metabolite stress response in the pathogen that had previously gone unnoticed. Under such conditions, the researchers identified the folate biosynthetic enzyme FolE2 as conditionally essential, an enzyme rare in bacteria that can be easily targeted.
By utilizing a strategy called chemical synthetic lethality, they effectively combined trimethoprim with a natural compound known as *dehydrocostus lactone* (DHL) to inhibit the FolE2 enzyme’s activity, disrupting the secondary response that the bacteria depend on for survival, all while selectively eliminating the pathogen without harming beneficial gut bacteria.
“In essence, we achieved the molecular equivalent of synthetic lethality, a well-known genetics phenomenon where two mutations are fatal only when combined,” Seyedsayamdost stated. “One molecule has no effect alone, the second molecule is harmless on its own, but when the two are combined — in this case, trimethoprim and DHL — the result is deadly. We successfully merged genetics with chemistry.”
The findings also indicate that this combination therapy strategy could be applied to fight a variety of organisms, leading to less harmful systemic treatments.
“Ultimately, I hope this research extends beyond *Burkholderia pseudomallei*,” added Zhang. “If we can apply this method to other pathogens, it could lead to new pathways for developing treatments that are not just effective but also considerate of our microbiome’s delicate balance.
“Understanding that our efforts could contribute to life-saving therapies for such a devastating illness is incredibly inspiring and fulfilling. That’s the broader goal that continues to drive my enthusiasm and hopes for the direction this research might take.”
