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

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.

Targeting heme oxygenase-1 and carbon monoxide for therapeutic modulation of inflammation

“…316 Both CORM2 and CORM3 exerted antibacterial activity against antibiotic-resistant strains of H. pylori . 319 Recent advances using PhotoCORMs demonstrate photoactivatable toxicity of these compounds toward E. coli bacteria. 301 CORMs may also find application in reducing gastrointestinal inflammation in various models including post-operative ileus and necrotizing enterocolitis.…”

Emerging Delivery Strategies of Carbon Monoxide for Therapeutic Applications: from CO Gas to CO Releasing Nanomaterials

“…For example, Nobre et al reported that the administration of CO gas into the growing cultures could cause significant impairment to the growth of Escherichia coli and Staphylococcus aureus . Recently, CORMs with the capacity of delivering CO directly to intracellular targets have been used as bactericides against a wide range of microorganisms, such as Pseudomonas aeruginosa , Mycobacterium tuberculosis , Helicobacter pylori , pathogenic Escherichia coli , and Neisseria gonorrhoeae . Importantly, CORMs were shown to be more potent bactericides than CO gas due to the accumulation of CORMs inside bacterial cells .…”

“…In detail, the half‐lives of CORM‐3 in distilled water, phosphate buffered saline, and human plasma were 98 h, 20.4 min, and 3.6 min, respectively . Cell and animal studies have confirmed that CORM‐3 possessed anti‐ischemia activity, anti‐inflammatory property, and broad‐spectrum antimicrobial effect . In spite of the remarkable biological functions, the main drawback of these solvent‐labile CORMs as a therapeutic agent is the lack of spatiotemporally restricted CO release, which may induce potential CO poisoning and therefore impede their clinical therapeutic utility.…”

Synergisms, Discrepancies and Interactions between Hydrogen Sulfide and Carbon Monoxide in the Gastrointestinal and Digestive System Physiology, Pathophysiology and Pharmacology

“…Interestingly, it has been reported that CO donors could exert antibacterial activity against Helicobacter pylori (H. pylori) [57]. Nowadays, the gastric colonization with H. pylori constitutes the major risk of gastric and duodenal ulcer diseases, mucosa-associated lymphoid tissue (MALT) lymphoma and even gastric adenocarcinoma [58].…”

“…Nowadays, the gastric colonization with H. pylori constitutes the major risk of gastric and duodenal ulcer diseases, mucosa-associated lymphoid tissue (MALT) lymphoma and even gastric adenocarcinoma [58]. Antimicrobial action of stimulated murine macrophages was enhanced by CORM-2 against H. pylori [57]. Moreover, CORM-2 impaired H. pylori respiration and inhibited H. pylori related urease activity [57], however, the role of H 2 S in H. pylori infection has not been fully recognized.…”