Antibiotic resistance in diarrhea-causing bacteria and its disruption of gut microbiota composition are health problems worldwide. The development of combinatory agents that increase the selective inhibitory effect (synergism) against diarrheagenic pathogens and, simultaneously, have a lowered impact (antagonism) or no negative action on the gut microbiota is therefore proposed as a new strategy efficient for chemotherapy against diarrheal conditions. In this study, the in vitro selective combinatory effect of ciprofloxacin with nitroxoline, sanguinarine, and zinc pyrithione, representing various classes of alkaloid-related compounds (nitroquinolines, benzylisoquinolines and metal-pyridine derivative complexes) against selected standard diarrhea-causing (Bacillus cereus, Enterococcus faecalis, Listeria monocytogenes, Shigella flexneri, and Vibrio parahaemolyticus) and gut-beneficial (Bifidobacterium adolescentis, Bifidobacterium animalis subsp. lactis, Bifidobacterium breve, Lactobacillus casei, and Lactobacillus rhamnosus) bacteria, was evaluated according to the sum of fractional inhibitory concentration indices (FICIs) obtained by the checkerboard method. The results showed that the individual combination of ciprofloxacin with nitroxoline, sanguinarine, and zinc pyrithione produced a synergistic effect against the pathogenic bacteria, with FICI values ranging from 0.071 to 0.5, whereas their antagonistic interaction toward the Bifidobacterium strains (with FICI values ranging from 4.012 to 8.023) was observed. Ciprofloxacin-zinc pyrithione produced significant synergistic action against S. flexneri, whereas a strong antagonistic interaction was observed toward B. breve for the ciprofloxacin-nitroxoline combination. These findings suggest that certain combinations of agents tested in this study can be used for the development of antidiarrheal therapeutic agents with reduced harmful action on the gastrointestinal microbiome. However, further studies focused on their pharmacological efficacy and safety are needed before they are considered for clinical trials. IMPORTANCE Diarrheal infections, which are commonly treated by antibiotics, are still responsible for over 4 to 5 million cases of human deaths annually. Moreover, the rising incidence of antibiotic resistance and its negative effect on beneficial bacteria (e.g., Bifidobacteria) of the gut microbial community are another problem. Thus, the development of selective agents able to inhibit diarrheal bacteria and, simultaneously, that have no negative impact on the gut microbiota, is important. Our results showed that individual combinations of ciprofloxacin with nitroxoline, sanguinarine, and zinc pyrithione produced synergism against the pathogenic bacteria, whereas their antagonistic interaction toward the beneficial strains was observed. The antagonism can be considered a positive effect contributing to the safety of the therapeutic agents, whereas their synergism against diarrheal bacteria significantly potentiates total antimicrobial efficacy. The certain combinations tested in this study can be used for the development of antidiarrheal agents with reduced harmful action on the gastrointestinal microbiome.

• Klíčová slova
• antagonism, antimicrobial agents, diarrhea, gut microbiota, selectivity, synergism,
• MeSH
• antibakteriální látky farmakologie   MeSH
• Bacteria MeSH
• benzylisochinoliny * MeSH
• Bifidobacterium MeSH
• ciprofloxacin farmakologie   MeSH
• lidé MeSH
• nitrochinoliny * MeSH
• obstipancia MeSH
• průjem farmakoterapie   MeSH
• pyridiny farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antibakteriální látky MeSH
• benzylisochinoliny * MeSH
• ciprofloxacin MeSH
• nitrochinoliny * MeSH
• nitroxoline MeSH Prohlížeč
• obstipancia MeSH
• pyridiny MeSH
• pyrithione zinc MeSH Prohlížeč
• sanguinarine MeSH Prohlížeč

Bacterial diarrhea remains a global health problem, especially in developing tropical countries. Moreover, dysbiosis caused by diarrheagenic bacteria and inappropriate antimicrobial treatment has been associated with intestinal carcinogenesis. Despite the rich tradition of the use of herbs for the treatment of gastrointestinal disorders in Cambodian and Philippine folk medicine, many of them have not yet been systematically studied for their in vitro selective inhibitory effects on intestinal bacteria and cells. In the present study, in vitro inhibitory activities of 35 ethanolic extracts derived from 32 Cambodian and Philippine medicinal plants were determined by broth microdilution method against 12 pathogenic bacteria. Furthermore, cytotoxicity against intestinal cancer cells (Caco-2 and HT-29) using thiazolyl blue tetrazolium bromide cytotoxicity assay and safety to six beneficial intestinal bacteria (bifidobacteria and lactobacilli) and intestinal normal cells (FHs 74 Int) were determined for the antimicrobially active extracts. Selectivity indices (SIs) were calculated among the averages of minimum inhibitory concentrations (MICs), half-maximal inhibitory concentrations (IC50), and 80% inhibitory concentrations of proliferation (IC80) for each type of the tested agents. The extracts of Artocarpus blancoi (Elmer) Merr. (Moraceae), Ancistrocladus tectorius (Lour.) Merr. (Ancistrocladaceae), and Pentacme siamensis (Miq.) Kurz (Dipterocarpaceae) produced significant growth-inhibitory effects (MICs = 32-512 μg/ml) against intestinal pathogenic bacteria at the concentrations nontoxic to normal intestinal cells (IC80 values >512 μg/ml; SIs = 0.11-0.2). Moreover, the extract of P. siamensis (Miq.) Kurz was relatively safe to beneficial bacteria (MICs ≥512 μg/ml; SI = 0.1), and together with A. blancoi (Elmer) Merr., they selectively inhibited intestinal cancer cells (IC50 values ≥51.98 ± 19.79 μg/ml; SIs = 0.3 and 0.6). Finally, a strong selective antiproliferative effect on cancer cells (IC50 values 37.89 ± 2.68 to 130.89 ± 13.99 μg/ml; SIs = 0.5) was exerted by Ehretia microphylla Lam. (Boraginaceae), Lagerstroemia cochinchinensis Pierre ex Gagnep. (Lythraceae), and Melastoma saigonense (Kuntze) Merr. (Melastomataceae) (leaves with flower buds). The results suggest that the above-mentioned species are promising materials for the development of new selective antibacterial and antiproliferative agents for the treatment of infectious diarrhea and associated intestinal cancer diseases. However, further research is needed regarding the isolation and identification of their active constituents.

• Klíčová slova
• Cambodia, Philippines, antibacterial, anticancer, diarrhea, medicinal plant,
• Publikační typ
• časopisecké články MeSH

A desirable attribute of novel antimicrobial agents for bacterial diarrhea is decreased toxicity toward host intestinal microbiota. In addition, gut dysbiosis is associated with an increased risk of developing intestinal cancer. In this study, the selective growth-inhibitory activities of ten phytochemicals and their synthetic analogs (berberine, bismuth subsalicylate, ferron, 8-hydroxyquinoline, chloroxine, nitroxoline, salicylic acid, sanguinarine, tannic acid, and zinc pyrithione), as well as those of six commercial antibiotics (ceftriaxone, ciprofloxacin, chloramphenicol, metronidazole, tetracycline, and vancomycin) against 21 intestinal pathogenic/probiotic (e.g., Salmonella spp. and bifidobacteria) bacterial strains and three intestinal cancer/normal (Caco-2, HT29, and FHs 74 Int) cell lines were examined in vitro using the broth microdilution method and thiazolyl blue tetrazolium bromide assay. Chloroxine, ciprofloxacin, nitroxoline, tetracycline, and zinc pyrithione exhibited the most potent selective growth-inhibitory activity against pathogens, whereas 8-hydroxyquinoline, chloroxine, nitroxoline, sanguinarine, and zinc pyrithione exhibited the highest cytotoxic activity against cancer cells. None of the tested antibiotics were cytotoxic to normal cells, whereas 8-hydroxyquinoline and sanguinarine exhibited selective antiproliferative activity against cancer cells. These findings indicate that 8-hydroxyquinoline alkaloids and metal-pyridine derivative complexes are chemical structures derived from plants with potential bioactive properties in terms of selective antibacterial and anticancer activities against diarrheagenic bacteria and intestinal cancer cells.

• Klíčová slova
• antibacterial, anticancer, diarrhea, plant compounds, selectivity,
• Publikační typ
• časopisecké články MeSH

Clostridium perfringens-induced necrotic enteritis is generally controlled by antibiotics. However, because of increasing antibiotic resistance, other antibacterial agents are required, preferably ones that do not affect the beneficial intestinal microbiota of the host. This study evaluated the in vitro selective growth-inhibitory effect of 8-hydroxyquinoline (8HQ) on C. perfringens vs. bifidobacteria in a medium containing chicken ileal digesta. Prior to the experiments, the minimum inhibitory concentrations of 8HQ and penicillin G were determined by broth microdilution assay. The minimum inhibitory concentration values of 8HQ for C. perfringens were 16-32 times lower than the values for bifidobacteria. Treatment of autoclaved and non-autoclaved chicken ileal digesta with 8HQ showed a selective anticlostridial effect. After incubation of C. perfringens with autoclaved ileal digesta for 3 h, all 8HQ concentrations tested (32-2048 μg/mL) significantly reduced C. perfringens bacterial count. In contrast, the same treatment had no or only a slight effect on bifidobacteria counts. Unlike 8HQ, penicillin G did not exhibit any selectivity. Similar results were obtained after incubation for 24 h. In non-autoclaved ileal digesta, all 8HQ concentrations tested significantly reduced C. perfringens bacterial counts after incubation for 30 min and 3 h, while no effect was observed on bifidobacteria. These results suggest that 8HQ may serve as a prospective veterinary compound for use against necrotic enteritis in poultry.

• MeSH
• antibakteriální látky farmakologie   MeSH
• Bifidobacterium účinky léků   MeSH
• Clostridium perfringens účinky léků   MeSH
• ileum mikrobiologie   MeSH
• klostridiové infekce prevence a kontrola   veterinární   virologie   MeSH
• kur domácí mikrobiologie   MeSH
• nemoci drůbeže prevence a kontrola   virologie   MeSH
• oxychinolin farmakologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antibakteriální látky MeSH
• oxychinolin MeSH