UB chemist leads $3 million NSF grant to find other causes of antimicrobial resistance

UB chemist Diana Aga has long researched how unchecked antibiotics in wastewater contribute to antimicrobial resistance (AMR). 

Water treatment plants don’t completely remove antibiotics from sewage before releasing them into waterways, which means that environmental bacteria and other microorganisms are constantly exposed to antibiotic residues and eventually develop resistance to the very drugs that have been designed to kill them.

But, Aga wonders — and a growing body of scientific evidence suggests — what if other chemicals are also to blame?

“Obviously, the release of antibiotics into the environment plays an important role in resistance development. However, other factors, including the presence of other drugs, like antidepressants, are important, as are metals and pesticides,” she says. “They all put evolutionary pressure on bacteria. To contend with AMR, we need to better understand the combined impact of these interactions.”

Aga, SUNY Distinguished Professor and director of the UB RENEW Institute, is the principal investigator on a $3 million grant from the National Science Foundation (NSF) to study chemicals that leak into the environment and exacerbate the emergence and spread of AMR.

The funding, of which UB will receive $1.4 million, is an NSF “Using the Rules of Life to Address Societal Challenges” (URoL:ASC) award. The program supports research that applies established scientific principles — in Aga’s case, bacterial evolution — across a broad array of living systems to tackle pressing societal concerns.

“Understanding factors contributing to antibiotic resistance is essential to preserving effective treatments and addressing health worldwide,” says Rep. Brian Higgins. “I have long supported these National Science Foundation investments in Congress. This is important work, and I am pleased to see University at Buffalo researchers standing out.”

While pharmaceutical science races to develop new antibiotics to replace those that have become ineffective, Aga says it’s also crucial for other scientists to uncover how AMR happens in the first place.

“New drugs may work great initially, but then the bacteria will develop resistance to them, too,” she says. “So, we need to understand the control mechanisms that we can use to mitigate or prevent entirely bacterial evolution that culminates in antimicrobial-resistant organisms.”

The World Health Organization has declared AMR one of the top-10 global public health threats. Bacterial “superbugs” that survive in the presence of antibiotics were linked to more than 5 million deaths worldwide in 2019, according to the Centers for Disease Control and Prevention. 

“It’s a significant public health threat because we are running out of medicines for curing people infected by pathogenic bacteria,” says Aga, Henry M. Woodburn Chair of Chemistry in the College of Arts and Sciences.

Ironically, antibiotics contribute to antimicrobial resistance. While antibiotics are crucial for killing bacteria and curing infections in humans and other animals, the bacteria that survive such treatment multiply and spread resistance genes to other bacteria. 

To safeguard against this, scientists need to know the minimum inhibitory concentration, which is the lowest amount of an antibiotic needed to stop the growth of a certain bacteria. However, Aga says some bacteria are mutating when exposed to antibiotics far below these levels. 

“Why? That is the question, and scientists have been investigating various mechanisms to understand how ‘superbugs’ develop and spread in the environment,” Aga says.

Aga hypothesizes this is because other chemicals are also pressuring bacteria to mutate. The genes that resist these chemicals can be the same genes that resist antibiotics or be located on the same mobile genetic elements.

One class of the chemicals that Aga’s team will investigate are heavy metals. Previous studies have linked metal pollution with high levels of antibiotic resistance. One of the more common examples of metal pollution — lead contamination — can be caused by corrosion of water service lines.

Another culprit may be antidepressants, which according to the CDC are taken by 13% of adults in the United States. Like antibiotics, water treatment plants typically don’t remove antidepressants from sewage. Aga has previously documented the buildup of antidepressants in the brains of Great Lakes fish.

Pesticides are another potential contributing factor. Aga previously uncovered pesticide contamination in the waters of Bangladesh.

In addition to chemicals, the team will also investigate what role climate change plays in the development of antimicrobial resistance. Disruptions to ecosystems may be putting additional pressure on bacteria, while high temperatures are linked with increased bacterial growth.

“Climate change is definitely playing a role in AMR,” Aga says. “However, we need to quantify the impact of weather disruptions on bacterial mutation to develop data-driven solutions.”

Wastewater treatment plants are designed to remove human excrement and excess nutrients such as nitrogen and phosphorus, but they are not designed to remove residues of antibiotics.

Even before antibiotic-filled water is released into waterways, antimicrobial resistance can emerge in the plant itself as bacteria and antibiotics mingle in the untreated sewage. 

Aga has previously conducted research to understand how wastewater treatment plants can be designed to remove antibiotics.

“One of the deliverables that we want from this current project is to be able to tell treatment plants the safe levels of chemical residues that can be discharged into waterways, as well as the best temperature range to limit spread of antimicrobial resistance at the treatment plant,” she says.

Co-investigator Shannon Seneca, a new assistant professor in the Department of Indigenous Studies and a faculty affiliate of RENEW, will study if outcomes from laboratory experiments will translate at scale in wastewater treatment plants.

At Iowa State University, Adina Howe, professor of agricultural and biosystems engineering, and Laura Jarboe, professor of chemical engineering, will study resistant genes of bacteria isolated from wastewater. Liqing Zhang, professor of bioinformatics at Virginia Tech, will use machine learning and data science to create models that will predict environmental conditions when bacteria will develop resistance.

The team’s research builds upon Aga’s work with RENEW, a multidisciplinary research institute focused on complex energy and environmental issues.

“RENEW draws upon the strengths of different disciplines to tackle persistent global problems — like antimicrobial resistance — and their related environmental equity challenges,” says Lisa Vahapoğlu, RENEW education and outreach director. “Through its research and activities, the institute also aims to advance projects of relevance to our community partners, and to create higher education pathways for people underrepresented in STEM disciplines. These priorities are manifest in the ‘NSF Using Rules of Life’ project.

“Diana and her team will bring together data science, analytical chemistry, microbiology and environmental engineering to understand the complex factors that drive the development of environmental antibiotic resistance, and translate these findings into useful tools for stakeholders,” Vahapoğlu explains. “This is the precise sort of convergent team research with community impact that RENEW aims to advance.”