RESUMO
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.
Assuntos
Benzilisoquinolinas , Nitroquinolinas , Humanos , Ciprofloxacina/farmacologia , Antidiarreicos , Piridinas/farmacologia , Bifidobacterium , Bactérias , Antibacterianos/farmacologia , Diarreia/tratamento farmacológicoRESUMO
Bacterial skin diseases of livestock could be a serious global threat, especially in association with overcoming bacterial resistance. Combinatory action of antimicrobial agents proves to be an effective strategy to overcome the problem of increasing antibiotic resistance of microorganisms. In this study, the in vitro combined effect of zinc pyrithione with gentamicin against bacterial skin pathogens of livestock (Staphylococcus aureus, Streptococcus agalactiae, and Streptococcus dysgalactiae) was evaluated according to the sum of fractional inhibitory concentration indices (FICI) obtained by checkerboard method. The results showed that a combination of zinc pyrithione with gentamicin produced a strong synergistic effect (p < 0.001) against all tested streptococcal strains (with FICI values ranging from 0.20 to 0.42). Compared to that, only three out of eight S. aureus strains were highly susceptible to the combination of antimicrobial agents at single concentration (0.25 µg/mL) of zinc pyrithione with range of FICI 0.35−0.43. These findings suggest that interference between agents tested in this study can be used for the development of future veterinary pharmaceutical preparations for the treatment of bacterial skin infections of livestock.