Polymyxins are a last-line-of-defense group of lipopeptide antibiotics that health-care workers turn to when other antimicrobials fail. But even these powerful drugs can lose their edge as bacteria gain resistance.
At the American Chemical Society Fall 2026 meeting, Erin Carlson, a chemical microbiologist at the University of Minnesota Twin Cities, presented data suggesting that 2-aminobenzothiazoles can act as adjuvants and disrupt polymyxin-resistant bacteria’s ability to sense and respond to the antibiotics.
Carlson presented the findings during a talk Monday morning in the Division of Biochemistry and Chemical Biology.
“Polymyxins are cationic molecules. They interact with the negatively charged cell envelope of bacteria—in particular a molecule called lipid A, which is phosphorylated,” Carlson said in an interview before her presentation. Bacteria can respond to polymyxins and gain resistance by installing cationic groups onto lipid A, preventing electrostatic attraction, she said.
Carlson has spent years working on two-component signaling systems in bacteria. One of the two components in the system is a histidine kinase, which detects environmental change and transfers a phosphate group to the second component, a response regulator. The response regulator then regulates the bacteria’s gene expression to turn on its defenses.
In theory, histidine kinase inhibitors (HKIs) could prevent bacteria from sensing antimicrobials and activating resistance mechanisms. So Carlson’s lab screened over 53,000 molecules for HKIs and identified 2-aminobenzothiazoles as promising candidates.
Some 2-aminobenzothiazoles “can even resensitize the bacteria by 16-32-fold,” acting as an adjuvant and essentially moving polymyxin sensitivity back to wild-type levels, Carlson said. Her data show that this resensitization works because the molecules prevent the modification of lipid A.
But her recent work indicates that the exact mechanism of action may be somewhat misunderstood, Carlson said. “We think that we’d be inhibiting a protein called PhoQ,” an important histidine kinase. “When we generated that protein [PhoQ] in vitro, these molecules are extremely poor inhibitors, so there is some disconnect between what’s actually happening in the cells and what’s happening in vitro, and that’s kind of where the project sits right now.”
Helen Blackwell, a chemical biologist at the University of Wisconsin–Madison who knows Carlson’s work well but didn’t participate in this research, said in an interview before Carlson’s presentation that HKIs are a tricky target. “Not a lot of people have gone after that. It’s just a hard problem.”
But the implications for pursuing histidine kinases in two-component systems could have big implications, Blackwell said. Such signaling systems “play really important roles in infection by a lot of really notorious pathogens,” she added. “They’re nonessential pathways. . . . If you knock down a two-component signaling system, typically you’re not going to kill the bacteria. Therefore, resistance development is going to be limited.”
Even though 2-aminobenzothiazoles don’t seem to inhibit PhoQ in vitro, Carlson is excited to figure out exactly why the molecules might be such good adjuvants. “I think one of the challenges of science is that you want your hypothesis to be true, and then you evaluate things and figure out, like, ‘Nope, biology is tricking us,’ ” she said. “So now we’re kind of going down a new road, and perhaps we’ll find a novel way that these molecules are resensitizing the bacteria to polymyxins.”
Max Barnhart is an assistant editor and life sciences reporter at C&EN.