Armeniaspirol A: a novel anti‐Helicobacter pylori agent

Abstract

Antibiotic resistance in Helicobacter pylori has been growing worldwide with current treatment regimens. Development of new compounds for treatment of H. pylori infections is urgently required to achieve a successful eradication therapy in the future. Armeniaspirols, a novel class of natural products isolated from Streptomyces armeniacus, have been previously identified as antibacterial agents against Gram-positive pathogens. In this study, we found that armeniaspirol A (ARM1) exhibited potent antibacterial activity against H. pylori, including multidrug-resistant strains, with MIC range values of 4-16 lg ml -1 . The underlying mechanism of action of ARM1 against H. pylori involved the disruption of bacterial cell membranes. Also, ARM1 inhibited biofilm formation, eliminated preformed biofilms and killed biofilm-encased H. pylori in a dose-dependent manner. In a mouse model of multidrug-resistant H. pylori infection, dual therapy with ARM1 and omeprazole showed efficient in vivo killing efficacy comparable to the standard triple therapy, and induced negligible toxicity against normal tissues. Moreover, at acidic pH 2.5, ARM1 exhibited a much more potent anti-H. pylori activity than metronidazole. Thus, these findings demonstrated that ARM1 is a novel potent anti-H. pylori agent, which can be developed as a promising drug lead for treatment of H. pylori infections.

Helicobacter pylori Biofilm-Related Drug Resistance and New Developments in Its Anti-Biofilm Agents

“…Moreover, a combination of ARM1 and omeprazole more effectively killed H. pylori in vivo compared to standard triple therapy in a mouse model of multidrug-resistant H. pylori infection. 12 The combination of DHT and omeprazole also showed superior H. pylori -killing effect than standard triple therapy, suggesting that DHT may be suitable anti- H. pylori drug when combined with a proton pump inhibitor. 57 From the above, it follows that natural products have great potential to combat H. pylori biofilms and to address the problem of drug resistance in H. pylori .…”

“…Majority of H. pylori strains are capable of forming biofilms in vivo and in vitro depending on the strain. 11 , 12 Clinical strains isolated from the gastric mucosa of patients have been reported to have higher capacity to form biofilm than other strains. 13 The formation of biofilms by H. pylori , like other bacteria, is divided into four steps: (1) attachment, (2) growth, (3) maturity, and (4) dispersal ( Figure 1 ).…”

“… 56–59 It is noteworthy that some of the natural products tested for anti-biofilm and antibacterial ability were carried out using H. pylori strains that were resistant to one or more drugs. 12 , 56 , 60 This suggests that some natural products have the potential to alleviate H. pylori multidrug resistance. Evidence from prior studies has indicated that H. pylori eradication therapy requires a combination of different antibiotics such as clarithromycin (CLR), levofloxacin (LVX), amoxicillin (AMX), metronidazole (MTZ), and tetracycline (TET).…”

Asclepain cI, a proteolytic enzyme from Asclepias curassavica L., a south American plant, against Helicobacter pylori

“…According to literature, 7-O-butylnaringenin (flavonoid) decreased the viable cell count of H pylori strains in 2 log units (Moon et al, 2013). Besides, armeniaspirol A, a product isolated from Streptomyces armeniacus led to a three-log decrease in viable cell count of H. pylori strains (Jia et al, 2022). On the other hand, we performed both optical and electron microscopy of treated and untreated H. pylori cells with asclepain cI.…”

Total synthesis and mechanism of action of the antibiotic armeniaspirol A

“…A recent study reported in vivo efficacy of 1 in a Helicobacter pylori mouse infection model, and the disruption of the H. pylori cell membrane was observed by electron microscopy after treatment with 1. 8 However, the understanding of armeniaspirol's activity has been hampered by the fact that their mechanism of action has been still unknown. Intriguingly, while we drafted this manuscript, Labana et al published the interaction of the armeniaspirol derivative 4 with the proteases ClpXP and ClpYQ – a mechanism that is different to the ones we report below (see discussion).…”