Solution NMR studies on Helicobacter pylori proteins for antibiotic target discovery

ABSTRACT

Introduction: Helicobacter pylori (H. pylori) is a well-known widespread pathogenic bacterium that survives in the extremely acidic conditions of the human gastric mucosa. The global prevalence of H. pylori-resistant antibiotics has become an emerging issue in the 21st century and has necessitated the development of novel antibiotic drugs. Many efforts have aimed to discover antibiotic target proteins of H. pylori based on its genome of more than 1600 genes.

Areas covered: This article highlights NMR spectroscopy as a valuable tool for determining the structure and dynamics of potential antibiotic-targeted proteins of H. pylori and evaluating their modes of interaction with native or synthetic binding partners. The residue-specific information on binding in solution provides a structural basis to identify and optimize lead compounds.

Expert opinion: NMR spectroscopy is a powerful method for obtaining details of biomolecular interactions with a broad range of binding affinities. This strength facilitates the identification of the binding interface of the encounter complex that plays an integral role in a variety of biological functions. This low-affinity complex is difficult to crystallize, which impedes structure determination using X-ray crystallography. Additionally, the relative binding affinities can be predicted from the type of spectral change upon binding. High-resolution NMR spectroscopy in combination with advanced computer simulation would provide more confidence in complex structures. The application of NMR to studies of the H. pylori protein could contribute to the development of these targeted novel antibiotics.

KEYWORDS:

• NMR spectroscopy
• Helicobacter pylori proteins
• antibiotic target
• tertiary structure
• biomolecular interaction
• dynamics

Article highlights

• 27 structures of relatively small proteins from H. pylori have been determined using solution-state NMR spectroscopy.

• NMR spectroscopy has the strength to examine biological interactions of H. pylori proteins in a wide spectrum of binding affinities.

• Advanced NMR techniques on the basis of nuclear spin relaxation and NOE have been used for dynamics studies of H. pylori proteins.

• Complex enzymatic reactions of H. pylori proteins can be quantified by changes in NMR signals of substrates and products

• Comprehensive NMR studies on the interaction between ligands and essential proteins of H. pylori could contribute to the development of novel antibiotic drugs.

• Toxin-antitoxin system of H. pylori has recently received attention as a novel antibiotic target.

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Declaration of interests

This work was supported by grants provided by the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF-2007-0057059, 2014K1A3A1A19067618, and 2015R1A2A1A05001894), and the 2015 BK21 plus Project for Medicine, Dentistry and Pharmacy. KY Lee has been supported, as a senior researcher, and BJ Lee, as a professor, by Seoul National University and the National Research Foundation of Korea (NRF). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.