Molecular structure intertwining with bacteria representing drug discovery.

Decoding Drug Resistance: How Understanding Bacterial Enzymes Can Lead to New Antibiotics

Elliot Brynn in Health & Wellness August 2025 • 4 min read.

"Researchers uncover the structure of a key enzyme in Neisseria gonorrhoeae, paving the way for targeted drug development to combat antibiotic resistance."

Neisseria gonorrhoeae, the culprit behind gonorrhea, remains a significant global health concern. The alarming rise of antibiotic-resistant strains threatens effective treatment, creating an urgent need for alternative therapeutic approaches. Scientists are now focusing on identifying and targeting essential bacterial enzymes to develop new drugs that can bypass resistance mechanisms.

One such enzyme is 4-hydroxy-tetrahydrodipicolinate reductase (DapB). DapB plays a vital role in the meso-diaminopimelate pathway, which is essential for bacteria to produce lysine, a building block for proteins and cell walls. Because mammals don't have this pathway, DapB is an ideal target for antibiotics – drugs that will selectively harm bacteria without affecting human cells.

A recent study published in Biochemical and Biophysical Research Communications unveils the first detailed structure of DapB from N. gonorrhoeae. This breakthrough provides crucial insights into how DapB interacts with essential molecules, offering a blueprint for designing drugs that can effectively shut down its function and combat gonorrhea.

A Closer Look at DapB: Structure and Function

Molecular structure intertwining with bacteria representing drug discovery.

The research team successfully determined the three-dimensional structure of NgDapB using X-ray crystallography. This allowed them to visualize the enzyme's architecture at a high resolution of 1.85 Ångströms, revealing key features of its structure.

Here's what they discovered about this essential enzyme:

Tetrameric Structure: Like other bacterial DapB enzymes, NgDapB assembles into a tetramer, a complex of four identical protein subunits. This structure is crucial for its function.
Two Key Domains: Each subunit contains two domains: a coenzyme-binding domain, which interacts with molecules like NADH and NADPH that provide the energy for the enzymatic reaction, and an oligomerization domain, responsible for assembling the tetramer.
Active Site Insights: The structure reveals important details about the active site, the region where the enzyme binds its substrate and carries out the chemical reaction. This information is essential for designing drugs that can specifically target and inhibit the enzyme.

The researchers also explored how NgDapB interacts with its coenzymes, NADH and NADPH, as well as a substrate analog called 2,6-pyridine dicarboxylic acid (2,6-PDC). 2,6-PDC mimics the natural substrate of DapB and acts as an inhibitor, binding to the active site and blocking the enzyme's activity. These interactions provided further clues about the enzyme's mechanism and potential drug targets.

The Future of Antibiotic Development

This structural understanding of NgDapB opens exciting new avenues for combating N. gonorrhoeae infections. By using the 3D structure as a guide, scientists can design molecules that:

<ul><li>Specifically bind to the active site of NgDapB, preventing it from carrying out its essential function.</li><li>Disrupt the tetrameric assembly of the enzyme, rendering it inactive.</li><li>Exploit the unique conformational changes that occur during the enzymatic reaction to create highly targeted inhibitors.</li></ul>

The battle against antibiotic resistance requires innovative strategies and a deep understanding of bacterial mechanisms. By illuminating the structure and function of DapB, this research brings us closer to developing new, effective antibiotics that can overcome resistance and safeguard public health.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.1016/j.bbrc.2018.07.147, Alternate LINK

Title: 4-Hydroxy-Tetrahydrodipicolinate Reductase From Neisseria Gonorrhoeae – Structure And Interactions With Coenzymes And Substrate Analog

Subject: Cell Biology

Journal: Biochemical and Biophysical Research Communications

Publisher: Elsevier BV

Authors: Swanandi Pote, Sarah E. Pye, Tyler E. Sheahan, Anna Gawlicka-Chruszcz, Karolina A. Majorek, Maksymilian Chruszcz

Published: 2018-09-01

Everything You Need To Know

Why is antibiotic resistance in Neisseria gonorrhoeae a major concern, and how are researchers trying to address it?

Neisseria gonorrhoeae has developed resistance to many antibiotics, making infections difficult to treat. Scientists are focusing on targeting essential bacterial enzymes, like 4-hydroxy-tetrahydrodipicolinate reductase (DapB), to develop new drugs that can bypass these resistance mechanisms. By understanding the structure of these enzymes, researchers can design drugs that specifically inhibit their function, offering a new approach to combatting gonorrhea.

What is the role of 4-hydroxy-tetrahydrodipicolinate reductase (DapB) in bacteria, and why is it considered a good target for new antibiotics?

4-hydroxy-tetrahydrodipicolinate reductase (DapB) is an enzyme essential for bacteria like Neisseria gonorrhoeae to produce lysine, a crucial building block for proteins and cell walls. Because humans don't have the same pathway to produce lysine, DapB makes an ideal target for antibiotics. Drugs targeting DapB can selectively harm bacteria without affecting human cells.

How did researchers determine the detailed structure of 4-hydroxy-tetrahydrodipicolinate reductase (NgDapB) from Neisseria gonorrhoeae, and what did they discover about its structure?

The recent study used X-ray crystallography to determine the three-dimensional structure of 4-hydroxy-tetrahydrodipicolinate reductase (NgDapB) from Neisseria gonorrhoeae at a high resolution of 1.85 Ångströms. This revealed that NgDapB assembles into a tetramer, with each subunit containing a coenzyme-binding domain and an oligomerization domain. It also provided detailed insights into the active site, where the enzyme binds its substrate.

What do we know about the interactions between 4-hydroxy-tetrahydrodipicolinate reductase (NgDapB) and other molecules, such as coenzymes and inhibitors, and why are these interactions important?

The structure of 4-hydroxy-tetrahydrodipicolinate reductase (NgDapB) shows how it interacts with coenzymes like NADH and NADPH, which provide energy for the enzymatic reaction. It also revealed how inhibitors like 2,6-pyridine dicarboxylic acid (2,6-PDC) bind to the active site, blocking the enzyme's activity. This understanding is crucial for designing drugs that can effectively inhibit DapB and disrupt bacterial function.

How can the structural understanding of 4-hydroxy-tetrahydrodipicolinate reductase (NgDapB) contribute to the development of new antibiotics to combat Neisseria gonorrhoeae?

Understanding the three-dimensional structure of 4-hydroxy-tetrahydrodipicolinate reductase (NgDapB) opens the door for designing new drugs that can specifically target and inhibit this enzyme in Neisseria gonorrhoeae. By using the 3D structure as a guide, scientists can create molecules that bind to the active site of NgDapB, preventing it from functioning properly and ultimately combating gonorrhea. This approach offers a promising strategy to overcome antibiotic resistance.