New insights into how bacteria manage DNA

Houston, TX - Apr 22, 2026

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New analytical methods developed at Baylor College of Medicine and collaborating institutions have increased our understanding of how bacteria manage DNA. The methods enabled researchers to uncover how the sequence, physical shape and flexibility of DNA guide the activity of an enzyme called DNA gyrase, which previously got all the credit for managing DNA. Their work uncovers that certain attributes of DNA are major players in this game. The study, which appeared in Nature Communications, has implications for antibiotic design.

Imagine DNA is like the coiled cord connecting the handset with the telephone of a traditional landline. DNA is supercoiled, or coiled about itself, and how much it is coiled is critically important for managing virtually all DNA activity. For example, if supercoiling is not managed, essential processes such as reading and copying DNA and cell division grind to a halt. Bacteria have DNA gyrase to prevent these problems, but many details of how gyrase works remain unknown.

The researchers had previously shown that DNA gyrase is wrapped inside supercoiled DNA loops. This is the first step of the process for managing DNA supercoiling. In the current study, they investigated what guides gyrase to specific DNA sites.

Earlier studies suggested that gyrase activity cannot be fully explained by recognizing a particular DNA sequence. "We focused on understanding how the shape of different DNA segments that bend or twist depending on their sequence, influence gyrase function," said corresponding author Dr. Lynn Zechiedrich, Kyle and Josephine Morrow Chair in Molecular Virology and Microbiology, professor in the Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology and member of Dan L Duncan Comprehensive Cancer Center, all at Baylor.

To study this, the researchers examined their two previously determined high-resolution structures of gyrase bound to a small circular DNA molecule using cryogenic electron microscopy (cryoEM). In one structure, the DNA wrapped tightly around part of the enzyme. In the other, it did not. Whether the enzyme bound a single DNA site in both structures and sometimes was wrapped by any other DNA sequence was unknown.

"3D reconstructions from cryoEM can provide atomic level detail of how large molecular complexes formed by DNA and proteins are organized and interact," said first and corresponding author Dr. Matthew Baker, currently an assistant professor of biochemistry and molecular biology at the University of Texas Health Science Center at Houston. "Knowing which parts of the DNA were interacting with specific parts of gyrase allowed us to better establish the physical properties governing this interaction. The challenge was that the resolution of the cryoEM structures was not clear enough to identify which DNA sequence or sequences bound to or wrapped around gyrase."

"We developed a new computational method that allowed us to identify the DNA sequence that bound to gyrase," said co-author Haley R. Johnson, graduate student in the program of Quantitative and Computational Biosciences, working in the Zechiedrich lab. "We were surprised to find that gyrase bound the same region of DNA from two different directions. In one structure, gyrase bound one side of the DNA and was wrapped. In the other structure, gyrase bound the other side of the DNA and was not wrapped."

In the wrapped structure, the DNA segment neighboring where gyrase bound was highly flexible. This allowed the DNA to wrap tightly around a part of the enzyme. Picture in your mind bending your elbow while wrapping your hand around a ball. That is the wrapped structure where both your elbow and your hand bend in the required directions - that results in gyrase doing its job. But if the region next to your elbow cannot bend in the right direction, then the DNA cannot wrap around a part of gyrase, and the enzyme cannot carry out its function.

"These observations suggest that gyrase binding is guided by specific shapes of DNA next to each other that are formed by certain sequences, favoring a bent binding site (your elbow) flanked by DNA that can wrap easily (your hand)," said co-author Silvia L. Summers, graduate student in the program of Chemical, Physical, and Structural Biology working in the Zechiedrich lab.

The researchers also conducted a detailed analysis of DNA deformability based on decades of structural data and identified the most flexible regions in DNA sequences. Altogether the findings suggest that rather than reading a sequence in DNA, gyrase recognizes DNA shapes and responds to DNA's ability to bend, unwind and wrap.

"Gyrase is an important antibiotic target." Zechiedrich said. "Understanding how gyrase selects DNA sites could help guide the design of antibiotics that disrupt gyrase's activity more precisely. Our work shows that, to gyrase, shapes and flexibility of DNA are as important as its genetic code, offering a more complete understanding of how this and perhaps other enzymes interact with DNA."

Other contributors to this work include Ryan A. Eckerty, Jonathan M. Fogg, Marlène Vayssières, Nils Marechal, Valérie Lamour and Wilma K. Olson. The authors are affiliated with one of the following institutions: Baylor College of Medicine, University of Texas Health Sciences Center at Houston, Georgia Institute of Technology, Université de Strasbourg, Hôpitaux Universitaires de Strasbourg and the State University of New Jersey.

This study was supported by the National Institutes of Health (NIH) (grants R35 GM141793, R01 GM34809 and R24 GM153869), the Welch Foundation (grant AU-2178-20240404), a training fellowship from the Houston Area Molecular Biophysics Program (NIH grant T32 GM150582 through the Gulf Coast Consortia). Further support was provided by the Agence Nationale de la Recherche grants ANR-19-CE11- 0001-01 and ANR-21-CE11-0040-01.