The Bactericidal Activity of Carbon Monoxide–Releasing Molecules against Helicobacter pylori

Ana F Tavares,Lígia M Saraiva,Marta C Justino,Margarida R Parente,Mónica Oleastro,Lígia S Nobre,Ivo G Boneca

doi:10.1371/journal.pone.0083157

Abstract

Helicobacter pylori is a pathogen that establishes long life infections responsible for chronic gastric ulcer diseases and a proved risk factor for gastric carcinoma. The therapeutic properties of carbon-monoxide releasing molecules (CORMs) led us to investigate their effect on H. pylori. We show that H. pylori 26695 is susceptible to two widely used CORMs, namely CORM-2 and CORM-3. Also, several H. pylori clinical isolates were killed by CORM-2, including those resistant to metronidazole. Moreover, sub-lethal doses of CORM-2 combined with metronidazole, amoxicillin and clarithromycin was found to potentiate the effect of the antibiotics. We further demonstrate that the mechanisms underpinning the antimicrobial effect of CORMs involve the inhibition of H. pylori respiration and urease activity. In vivo studies done in key cells of the innate immune system, such as macrophages, showed that CORM-2, either alone or when combined with metronidazole, strongly reduces the ability of H. pylori to infect animal cells. Hence, CORMs have the potential to kill antibiotic resistant strains of H. pylori.

Highlights

Helicobacter pylori is a pathogen that colonizes the gastric mucosa of humans and is ubiquitous in over half the world’s population
Helicobacter pylori Viability Is Inhibited by carbon-monoxide releasing molecules (CORMs) To examine how CORMs affect the growth of H. pylori 26695, CORM-2 and CORM-3 were added to cultures growing in BHIbCD under microaerobic conditions
The current work reveals that CORMs are effective against H. pylori with CORM-2 being more effective than CORM-3

Summary

Introduction

Helicobacter pylori is a pathogen that colonizes the gastric mucosa of humans and is ubiquitous in over half the world’s population. H. pylori establishes lifelong infections that are the major cause of gastric and duodenal ulcer diseases and malignant gastric cancer [1]. H. pylori uses several factors that enable colonization [2]. The more widely used antibiotics for treatment of H. pylori are metronidazole, clarithromycin, amoxicillin and tetracycline [5]. Infections with H. pylori are usually treated with a combination of drugs, which consists of two or three antibiotics together with an acid-suppressive drug (a proton pump inhibitor, e.g. omeprazole) [5]. The efficacy of these multiple antibiotic therapies is decreasing mainly due to the crescendo occurrence of antibiotic-resistant H. pylori strains. Metronidazole resistant strains are a major cause of H. pylori treatment failure [6]

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Conclusion