Cristina Landeta, an IU assistant professor studying how bacteria build and maintain their cell envelopes, has received two grants—from the National Institutes of Health (NIH) and the Cystic Fibrosis Foundation (CFF)—to support her lab’s work on oxidative protein folding and its potential as a target for new antibiotics.
Landeta’s research focuses on how proteins acquire disulfide bonds—covalent linkages between cysteine residues that are essential for the structure and function of many exported proteins in bacteria and other organisms. These bonds are critical for processes ranging from cell envelope assembly, an important contributor to intrinsic antibiotic resistance, to interactions with the environment. Despite their importance, many aspects of how disulfide bonds form and function in complex bacterial systems remain poorly understood.
One of the awards, a five-year NIH R35 grant, will support a comprehensive investigation into the fundamental principles governing disulfide bond formation in living cells. Using model organisms such as Escherichia coli and Mycobacterium smegmatis, Landeta’s team will examine how bacteria generate disulfide bonds, identify which proteins depend on these bonds in complex cell envelopes, and determine how different oxidoreductase enzymes recognize specific substrates. This work integrates bacterial genetics, chemical genetics, and biochemistry to uncover new mechanisms of oxidative protein folding and expand understanding of protein maturation across diverse cellular environments.
A second award from the Cystic Fibrosis Foundation will support efforts to generate critical preliminary data for a future NIH R01 submission. This project focuses on translating fundamental discoveries into potential therapeutic strategies by identifying and characterizing small molecules that inhibit bacterial enzymes responsible for disulfide bond formation. Leveraging an E. coli-based screening platform, the team will evaluate candidate compounds for their ability to penetrate bacterial membranes, selectively target bacterial enzymes, and avoid activity against human counterparts. The research will also assess how disrupting disulfide bond formation impacts the structure and function of cell envelopes in both Gram-negative bacteria and mycobacteria.
“Disulfide bond formation is a fundamental biological process that is still not fully understood, particularly in organisms with complex cell envelopes,” Landeta said. “By combining mechanistic studies with inhibitor discovery, we aim to uncover new biology and lay the groundwork for developing novel antibacterial strategies.”
Landeta is currently recruiting researchers interested in contributing to these efforts. More information about available positions can be found on the Academic Careers at IU webpage.
Together, these projects will provide new insight into the molecular mechanisms that shape bacterial cell envelopes and identify vulnerabilities that could be exploited to combat drug-resistant infections.
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