Identification of Antimotilins, Novel Inhibitors of Helicobacter pylori Flagellar Motility That Inhibit Stomach Colonization in a Mouse Model

Suerbaum, Sebastian; Coombs, Nina; Patel, Lubna; Pscheniza, Dimitri; Falk, Christine S.; Gruber, Achim D.; Kershaw, Olivia; Chhatwal, Patrick; Brönstrup, Mark; Bilitewski, Ursula; Josenhans, Christine

doi:10.1128/mbio.03755-21

Cited by 9 publications

(4 citation statements)

References 80 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The eradication therapies of H. pylori using antibiotics induce a high selection pressure leading to the acquisition of antibiotic resistance that can be transmitted between different strains and other members of the microbiome (24,(48)(49)(50)(51). Targeting the nonessential virulence factors that the bacteria use to infect the host is an alternative approach to reduce the pressure of selection induced by antibiotics (52)(53)(54)(55)(56). In this study we have characterized the binding site of Cagα inhibitor 1G2 using X-ray crystallography and mutagenesis suggesting a unique mechanism of inhibition via a binding site that is distinct from the ATPase active site.…”

Section: Discussionmentioning

confidence: 99%

Structure-based design of small molecule inhibitors of the cagT4SS ATPase Cagα of Helicobacter pylori

Morin,

Verma,

Arya

et al. 2023

Preprint

View full text Add to dashboard Cite

We here describe the structure-based design of small molecule inhibitors of the type IV secretion system ofHelicobacter pylori. The secretion system is encoded by the□cag□pathogenicity island, and we chose Cagα, a hexameric ATPase and member of the family of VirB11-like proteins, as target for inhibitor design. We first solved the crystal structure of Cagα in a complex with the previously identified small molecule inhibitor 1G2. The molecule binds at the interface between two Cagα subunits and mutagenesis of the binding site identified Cagα residues F39 and R73 as critical for 1G2 binding. Based on the inhibitor binding site we synthesized 98 small molecule derivates of 1G2 to improve binding of the inhibitor. We used the production of interleukin-8 of gastric cancer cells duringH. pyloriinfection to screen the potency of inhibitors and we identified five molecules (1G2_1313, 1G2_1338, 1G2_2886, 1G2_2889 and 1G2_2902) that have similar or higher potency than 1G2. Differential scanning fluorimetry suggested that these five molecules bind Cagα, and enzyme assays demonstrated that some are more potent ATPase inhibitors than 1G2. Finally, scanning electron microscopy revealed that 1G2 and its derivatives inhibit the assembly of T4SS-determined extracellular pili suggesting a mechanism for their anti-virulence effect.

show abstract

Section: Discussionmentioning

confidence: 99%

Structure-based design of small molecule inhibitors of the cagT4SS ATPase Cagα of Helicobacter pylori

Morin,

Verma,

Arya

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…The direction of movement is controlled by chemotaxis and energy taxis, enabling bacteria orientation through pH and bicarbonate (and possibly other) gradients in the gastric mucus 112 . Motility can be inhibited in vitro by small molecule compounds that reduce H. pylori colonization density, which may be a future treatment approach 113 .…”

Section: Bacterial Factors Involved In Colonization and Pathogenesismentioning

confidence: 99%

Helicobacter pylori infection

Malfertheiner

Camargo

El-Omar

et al. 2023

Nat Rev Dis Primers

Self Cite

146

View full text Add to dashboard Cite

Helicobacter pylori infection causes chronic gastritis, which can progress to severe gastroduodenal pathologies, including peptic ulcer, gastric cancer and gastric mucosa-associated lymphoid tissue lymphoma. H. pylori is usually transmitted in childhood and persists for life if untreated. The infection affects around half of the population in the world but prevalence varies according to location and sanitation standards. H. pylori has unique properties to colonize gastric epithelium in an acidic environment. The pathophysiology of H. pylori infection is dependent on complex bacterial virulence mechanisms and their interaction with the host immune system and environmental factors, resulting in distinct gastritis phenotypes that determine possible progression to different gastroduodenal pathologies. The causative role of H. pylori infection in gastric cancer development presents the opportunity for preventive screen-and-treat strategies. Invasive, endoscopy-based and non-invasive methods, including breath, stool and serological tests, are used in the diagnosis of H. pylori infection. Their use depends on the specific individual patient history and local availability. H. pylori treatment consists of a strong acid suppressant in various combinations with antibiotics and/or bismuth. The dramatic increase in resistance to key antibiotics used in H. pylori eradication demands antibiotic susceptibility testing, surveillance of resistance and antibiotic stewardship.

show abstract

“…Moreover, prior studies have substantiated that the administration of active 2, an anti-motilin agent, effectively impedes the colonization of H. pylori in a murine model by suppressing flagellar motility. Consequently, this compound exhibits potential as an adjunct to the conventional antibiotic-based combination therapy for the treatment and eradication of H. pylori infection ( Suerbaum et al., 2022 ).…”

Section: Pathogenesismentioning

confidence: 99%

Helicobacter pylori infection: a dynamic process from diagnosis to treatment

Sun,

Yuan,

Zhou

et al. 2023

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

Helicobacter pylori, a gram-negative microaerophilic pathogen, causes several upper gastrointestinal diseases, such as chronic gastritis, peptic ulcer disease, and gastric cancer. For the diseases listed above, H. pylori has different pathogenic mechanisms, including colonization and virulence factor expression. It is essential to make accurate diagnoses and provide patients with effective treatment to achieve positive clinical outcomes. Detection of H. pylori can be accomplished invasively and noninvasively, with both having advantages and limitations. To enhance therapeutic outcomes, novel therapeutic regimens, as well as adjunctive therapies with probiotics and traditional Chinese medicine, have been attempted along with traditional empiric treatments, such as triple and bismuth quadruple therapies. An H. pylori infection, however, is difficult to eradicate during treatment owing to bacterial resistance, and there is no commonly available preventive vaccine. The purpose of this review is to provide an overview of our understanding of H. pylori infections and to highlight current treatment and diagnostic options.

show abstract

Identification of Antimotilins, Novel Inhibitors of Helicobacter pylori Flagellar Motility That Inhibit Stomach Colonization in a Mouse Model

Cited by 9 publications

References 80 publications

Structure-based design of small molecule inhibitors of the cagT4SS ATPase Cagα of Helicobacter pylori

Structure-based design of small molecule inhibitors of the cagT4SS ATPase Cagα of Helicobacter pylori

Helicobacter pylori infection

Helicobacter pylori infection: a dynamic process from diagnosis to treatment

Contact Info

Product

Resources

About