Antimicrobial resistance (AMR) is a growing global threat. Experts warn that by 2050, up to 10 million deaths could be caused by resistant infections, matching the current annual global death toll from cancer. The World Health Organization (WHO) has estimated that 4.9 million deaths annually are already associated with AMR, while a 2022 study in The Lancet found that in 2019, 1.27 million deaths were the direct result of drug-resistant bacterial infections.
Although antibacterial research and preclinical development are expanding, the clinical pipeline remains thin. WHO data show that the number of antibacterials in clinical development has fallen from 97 in 2023 to 90 in 2025 — and only five are effective against at least one of the WHO’s “critical” bacterial pathogens, the highest-priority group of bacteria for which treatment options are already severely limited.
When we think of bacteria, we really do have to think of the membranes and how hard it is to get drugs across them — especially for gram-negative bacteria, which have two very different membranes.
- Heather Pinkett, Northwestern University
The few antibiotics that have reached the clinic in recent years are mostly derivatives of existing drugs, leaving them vulnerable to the same resistance mechanisms that bacteria have already evolved. In fact, it wasn’t until March 2025 that the FDA approved gepotidacin (Blujepa), the first oral antibiotic with a novel mechanism in nearly 30 years.
At the European Laboratory Research & Innovation Group (ELRIG) 2025 conference, DDN spoke with Heather Pinkett, a structural biologist at Northwestern University, whose research is shedding light on one of the least understood aspects of bacterial resistance: the membrane proteins that determine which molecules can enter or exit a bacterial cell. Pinkett’s work focuses in particular on ABC (ATP-binding cassette) transporters, a large and diverse family of proteins that use ATP to move compounds across membranes.
“When we think of bacteria,” Pinkett told DDN, “we really do have to think of the membranes and how hard it is to get drugs across them — especially for gram-negative bacteria, which have two very different membranes.”
How bacteria fight back
One focus of Pinkett’s research is non-typeable Haemophilus influenzae (NTHi), a common cause of middle ear infections in children. While healthy adults often clear these infections through innate immunity, children are frequently prescribed antibiotics such as amoxicillin. However, NTHi has rapidly developed resistance to many first-line treatments and is spreading at an alarming rate.
Pinkett’s team studies peptide transporters, which shuttle small molecules across bacterial membranes. One key group of these molecules are antimicrobial peptides (AMPs) — small peptides produced by the immune system to kill invading microbes.
These peptide transporters fall into several families based on their structure and sequence identity, including Dpp, Opp, and Sap. Dpp and Opp primarily bring in nutrient peptides that the bacteria use for growth. The Sap system, however, is more specialized. In NTHi, it helps the bacterium take up and neutralize AMPs, allowing it to survive the host immune response.
“What we think it’s able to do is open its binding cavity and recognize a specific sequence in AMPs,” Pinkett explained. “When we cut the peptides into smaller segments and tested them, we found that the transporter binds to a tiny region — just three amino acids, R-R-Y — within the loop of the AMP. That tells us it’s able to grab onto a very specific sequence even though it’s transporting the whole AMP.”
The therapeutic potential
By mutating key binding residues in the Sap transporter, Pinkett’s group was able to reduce its affinity for AMPs, making it more vulnerable to the host’s natural immune defenses. Building on this insight, they used peptidomimetic libraries, docking studies, thermal shift assays, and binding experiments to identify molecules that could target the transporter — creating molecular roadblocks or Trojan horses.
These approaches may either block Sap’s ability to neutralize AMPs or co-opt the transporter to smuggle drugs directly into the bacteria, turning a bacterial defense mechanism into a therapeutic advantage.
“When we tested smaller peptide fragments in binding assays, we saw that some were much more effective than others,” said Pinkett. “Their association and dissociation rates varied dramatically — some bound slowly but came off quickly, others bound fast and didn’t release. That kind of kinetic difference can determine whether a peptide is transported or just binds without being transported across the membrane.”
This specificity is actually a huge advantage: It means you can design molecules that target one species without affecting others.
- Heather Pinkett, Northwestern University
Understanding these mechanisms is crucial for developing new antimicrobials that can target bacteria in ways that are more difficult for them to develop resistance against. Pinkett also described how this knowledge could enable species-specific targeting.
“When we think of the Sap transporter specifically, and we look at it in different strains of bacteria, they all take up different peptides,” Pinkett explained. “For example, in NTHi, Sap takes up alpha and beta defensins, whereas in Escherichia coli, it binds a completely different AMP. This specificity is actually a huge advantage: It means you can design molecules that target one species without affecting others.”
Next-generation antimicrobials
Simply modifying existing antibiotics is unlikely to keep pace with bacterial resistance. To truly stay ahead, researchers need to develop entirely novel compounds, including de novo drugs that break from conventional design principles. Modern computational tools and machine learning are more than capable of accelerating this process, allowing scientists to model bacterial targets, predict resistance pathways, and design antibiotics that are less likely to fail.
“With the emergence of machine learning, we now have the potential to reduce the number of AMR-related deaths,” Pinkett said. “We can design novel drugs while simultaneously predicting how bacteria will evolve. Ideally, we can anticipate resistance and develop the next drug before the bacteria become resistant.”
In the race against AMR, ABC transporters represent both a formidable bacterial defense and a promising therapeutic target. With innovative structural biology, molecular design, and strategic funding, the fight against AMR could move from reactive to proactive.
