To secure its grip on the stomach wall, Helicobacter pylori (H. pylori) relies on adhesin proteins, the best-studied of which is BabA. Until recently, BabA has managed to hold its structural secrets as tightly as it latches onto the Lewisb sugars of the gastric mucosa. Holding fast to its structural secrets, H. pylori has managed to hang tough as a disease-causing bacterium, resisting natural mechanisms that would brush aside less tenacious pathogens, giving itself the chance to develop resistance to antibiotics, forming colonies that cause peptic ulceration, and gastric cancer.
Now, however, a closely held adhesin secret is out, thanks to research conducted by scientists from the University of Nottingham and Astra Zeneca. These scientists suggest that by breaking the grip H. pylori had on its BabB secret, they are poised to break the bacterium’s grip on the stomach wall.
Think of BabB as a sort of arm that reaches out from the H. pylori membrane. At the end of this arm, the scientists say, there is a binding site that is a sort of hand, a hand that relies on multiple hydrogen bonds to take hold of Lewisb. According to the scientists, disrupting multiple hydrogen bonds would be like peeling back the H. pylori hand finger by finger.
This suggestion appeared August 14 in the journal Science Advances, in an article entitled, “Structural basis of Lewisb antigen binding by the Helicobacter pylori adhesin BabA.”
“We present the crystal structure of the extracellular domain of BabA, from H. pylori strain J99, in the absence and presence of Leb at 2.0- and 2.1-Å resolutions, respectively,” wrote the authors. “BabA is a predominantly α-helical molecule with a markedly kinked tertiary structure containing a single, shallow Leb binding site at its tip within a β-strand motif. …. Binding is mediated by a network of hydrogen bonds between Leb Fuc1, GlcNAc3, Fuc4, and Gal5 residues and a total of eight BabA amino acids (C189, G191, N194, N206, D233, S234, S244, and T246) through both carbonyl backbone and side-chain interactions.”
Essentially, the scientists found that right BabA, right at its tip, has a specific groove. This molecular groove enables BabA to securely attach to Lewisb using a network of hydrogen bonds. This network appears to be finely tuned. That is, if a few of the hydrogen bonds are disrupted, the network doesn't function. Binding can no longer occur.
The structural model was validated through the generation of two BabA variants, one of which contained an N206A substitution, and one of which contained both D233A and S244A substitutions. These substitutions, reported the authors, resulted in a reduction of binding affinity to Lewisb (in the case of N206A) and complete loss of binding affinity to Lewisb (in the case of D233A/S244A).
This study now forms the foundation for future research between the University of Nottingham and AstraZeneca R&D into “anti-adhesion strategies” that would work by clearing H. pylori out of the stomach through dislodging the bacterium off the stomach wall using BabA:Lewisb inhibitors. Such novel strategies are needed to help treat H. pylori infections, which are globally gaining resistance to conventional antibiotic therapies.
“Because BabA is unique to H. pylori, we can specifically target, and hopefully eradicate, this bacterium without affecting the other good bacteria in our normal flora,” said the study’s first author, Naim Hage, Ph.D., a postdoc at Nottingham. “If successful, this therapeutic strategy will also be extremely useful for treating H. pylori infections that are already resistant to antibiotics.”
The principal investigator behind the project, Franco Falcone, Ph.D., added: “While this study answers long-standing questions about how H. pylori colonizes the stomach, it represents the very first step in the development of novel therapies. The next few years of laboratory-based research will be crucial to determine if an anti-BabA adhesion approach is viable and can progress to clinical development. A similar approach is already showing promising results for the treatment of urinary tract infections in preclinical models.”