Repurposing bioactive aporphine alkaloids as efflux pump inhibitors
Ontology highlight
ABSTRACT:
ORGANISM(S): Bacillus subtilis subsp. subtilis str. 168
PROVIDER: GSE106296 | GEO | 2020/10/09
REPOSITORIES: GEO
Similar Datasets
Project description:Repurposing bioactive aporphine alkaloids as efflux pump inhibitors
| PRJNA416141 | ENA
Project description:In the current study, RNA sequencing was used to comparatively elaborate the activities and the effects of the alkaloids, boldine, bulbocapnine, and roemerine along with the well-known antibacterial alkaloid berberine on Bacillus subtilis cells.
2018-07-17 | GSE104946 | GEO
Project description:Candida species have a major role in nosocomial infections leading to high morbidity and mortality. Increased resistance to various antifungals, especially azoles is a significant problem. One of the main mechanisms for azole resistance is the up-regulation of efflux pump genes including CDR1 and MDR1. In the current study, clinical Candida isolates were identified to the species level and the antifungal susceptibility (AFS) of different Candida species was determined by disk diffusion method. Furthermore, the main mechanisms of azole resistance were investigated. Finally, haloperidol and pantoprazole were tested for their potential synergistic effect against fluconazole-resistant isolates. One hundred and twenty-two Candida clinical isolates were used in this study. 70 isolates were Candida albicans (57.4%), the non-albicans Candida species include: C. krusei (20.5%), C. tropicalis (6.6%), C. parapsilosis (5.7%), C. dubliniensis (4.9%) and C. glabrata (4.9%). The AFS testing showed that resistance to fluconazole and voriconazole were 13.1% (n = 16) and 9.8% (n = 12), respectively. Among the 16 resistant isolates, eight isolates (50%) were strong biofilm producers, seven (43.8 %) formed intermediate biofilm and one had no biofilm. All resistant strains overexpressed efflux pumps. Using RT-PCR, the efflux genes CDR1, MDR1 and ABC2 were over-expressed in azole resistant isolates. Haloperidol-fluconazole and pantoprazole-fluconazole combinations reduced the MIC of fluconazole in resistant isolates. The current study showed an increase in azole resistance of Candida species. The majority of resistant isolates form biofilm, and overexpress efflux pumps. Pantoprazole and Haloperidol showed a noteworthy effect as efflux pump inhibitors which oppose the fluconazole resistance in different Candida species.
| S-EPMC9051972 | biostudies-literature
Project description:The aim of this study was to explore whether, and if so, how Bacillus subtilis KC1 can enhance the growth performance of broilers that have been adversely affected by Mycoplasma gallisepticum (MG) infection. A total of 96 1-day-old male broilers were randomly divided into 4 groups: the control group (basal diet), the MG group (basal diet + MG challenge), the Bacillus subtilis KC1 group (basal diet + Bacillus subtilis KC1 supplementation), the Bacillus subtilis KC1 + MG group (basal diet + Bacillus subtilis KC1 supplementation + MG challenge). The trial lasted 42 days, and the results showed that the MG group had significantly reduced body weight and average daily gain, as well as increased feed conversion ratio of broilers, compared to the control group. Dietary supplementation with Bacillus subtilis KC1 significantly improved the growth performance of MG-infected broilers. In addition, dietary supplementation with Bacillus subtilis KC1 significantly improved oxidative stress and inflammatory response markers, characterized by increased superoxide dismutase levels and reduced levels of malondialdehyde, interleukin-1β, and tumor necrosis factor-α. Furthermore, both metabolomics and transcriptomics analyses indicated that MG infection markedly disrupted amino acid metabolism in broilers, whereas Bacillus subtilis KC1 supplementation alleviated the abnormal amino acid metabolism caused by MG infection. These results suggested that Bacillus subtilis KC1 may alleviate the poor growth performance caused by MG infection in broilers by improving amino acid metabolism.
2024-10-23 | GSE273913 | GEO
Project description:Managing antibiotic resistance is a significant challenge in modern pharmacotherapy. While molecular analyses have identified efflux pump expression as an essential mechanism underlying multidrug resistance, the targeted drug development has occurred slower. Thus, considering the verification that terpenes can enhance the activity of antibiotics against resistant bacteria, the present study gathered evidence pointing to these natural compounds as bacterial efflux pump inhibitors. A systematic search for manuscripts published between January 2007 and January 2022 was carried out using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol and the following search terms: "Terpene"; AND "Efflux pump"; and "Bacteria." From a total of 101 articles found in the initial search, 41 were included in this review. Seventy-five different terpenes, 63 bacterial strains, and 22 different efflux pumps were reported, with carvacrol, Staphylococcus aureus SA-1199B, and NorA appearing most frequently mentioned terpene, bacterial strain, and efflux pump (EP), respectively. The Chi-Squared analysis indicated that terpenes are significantly effective EP inhibitors in Gram-positive and Gram-negative strains, with the inhibitory frequency significantly higher in Gram-positive strains. The results of the present review suggest that terpenes are significant efflux pump inhibitors and, as such, can be used in drug development targeting the combat of antibacterial resistance.
| S-EPMC9606600 | biostudies-literature
Project description:Interventions: A:Naught;B:Live Bacillus licheniformis capsule;C:Live Combined Bacillus Subtilis and Enterocoocus Faecium Enteric-coated Capsules;D:Triple Viable Capsules Dissolving at Intestines
Primary outcome(s): Overall survival
Study Design: Parallel
| 83346 | ecrin-mdr-crc
Project description:Staphylococcus aureus is a versatile human commensal bacteria and pathogen that causes various community and hospital-acquired infections. The S. aureus efflux pump NorA which belongs to the major facilitator superfamily, confers resistance to a range of substrates. Many efflux pump inhibitors (EPIs) have been discovered, but none is clinically approved due to their undesirable toxicities. In this study, we have screened clinically approved drugs for possible NorA EPI-like activity. We identified six drugs that showed the best efflux pump inhibition in vitro, with a fractional inhibitory concentration index of ≤0.5, indicating synergism with hydrophilic fluoroquinolones. The mechanistic validation of efflux inhibitory potential was demonstrated in ethidium bromide-based accumulation and efflux inhibition assays. We further confirmed the functionality of EPIs by norfloxacin accumulation assay depicting more realistic proof of the conjecture. None of the EPIs disturbed membrane function or depleted the ATP synthesis levels in bacteria. Both raloxifene and pyrvinium displayed an increase in bactericidal activity of ciprofloxacin in time-kill kinetics, prolonged its post-antibiotic effect, and reduced the frequency of spontaneous resistant mutant development. The combination of EPIs with ciprofloxacin caused significant eradication of preformed biofilms. Moreover, in the murine thigh infection model, a single dose of pyrvinium combined with ciprofloxacin reduced the bacterial burden significantly compared to untreated control and ciprofloxacin alone, indicating the efficacy of the combination. Conclusively, this study represents approved drugs that can be repurposed and combined with antibiotics as NorA EPIs, having anti-biofilm properties to treat severe S. aureus infections at clinically relevant concentrations. IMPORTANCE Staphylococcus aureus is a frequent pathogen bacterium and the predominant cause of worsened nosocomial infections. Efflux pumps contribute to drug efflux and are reportedly associated with biofilm formation, thereby promoting difficult-to-treat biofilm-associated S. aureus infections. One strategy to combat these bacteria is to reduce active efflux and increase pathogen sensitivity to existing antibiotics. Repurposing approved drugs may solve the classical toxicity issues with previous efflux pump inhibitors and help reach sufficient plasma concentrations. We describe the in silico-based screening of FDA-approved drugs that identified six different molecules able to inhibit NorA pump (Major Facilitator Superfamily). Our study highlights that these compounds bind to and block the activity of the NorA pump and increase the sensitivity of S. aureus and methicillin-resistant S. aureus to fluoroquinolones. These drugs combined with fluoroquinolones significantly reduced the preformed biofilms and displayed significant efficacy in the murine thigh infection model when compared to untreated control and ciprofloxacin alone.
| S-EPMC8672906 | biostudies-literature
Project description:Antibiotic resistance is a major threat to human welfare. Inhibitors of multidrug efflux pumps (EPIs) are promising alternative therapeutics that could revive activities of antibiotics and reduce bacterial virulence. Identification of new druggable sites for inhibition is critical for the development of effective EPIs, especially in light of constantly emerging resistance. Here, we describe EPIs that interact with periplasmic membrane fusion proteins, critical components of efflux pumps that are responsible for the activation of the transporter and the recruitment of the outer-membrane channel. The discovered EPIs bind to AcrA, a component of the prototypical AcrAB-TolC pump, change its structure in vivo, inhibit efflux of fluorescent probes, and potentiate the activities of antibiotics in Escherichia coli and other Gram-negative bacteria. Our findings expand the chemical and mechanistic diversity of EPIs, suggest the mechanism for regulation of the efflux pump assembly and activity, and provide a promising path for reviving the activities of antibiotics in resistant bacteria.
| S-EPMC5553321 | biostudies-literature
Project description:Comparison of the Bacillus cereus with overexpressed Bacillus subtilis ComK (Bacillus cereus pNWcomKBsu) vs Bacillus cereus carrying empty plasmid (Bacillus cereus pNW33N)
2011-07-28 | GSE27265 | GEO
Project description:Adaptive antibiotic resistance is a newly described phenomenon by which Acinetobacter baumannii induces efflux pump activity in response to host-associated environmental cues that may, in part, account for antibiotic treatment failures against clinically defined susceptible strains. To that end, during adaptation to growth in human serum, the organism induces approximately 22 putative efflux-associated genes and displays efflux-mediated minocycline tolerance at antibiotic concentrations corresponding to patient serum levels. Here, we show that in addition to minocycline, growth in human serum elicits A. baumannii efflux-mediated tolerance to the antibiotics ciprofloxacin, meropenem, tetracycline, and tigecycline. Moreover, using a whole-cell high-throughput screen and secondary assays, we identified novel serum-associated antibiotic efflux inhibitors that potentiated the activities of antibiotics toward serum-grown A. baumannii. Two compounds, Acinetobacter baumannii efflux pump inhibitor 1 (ABEPI1) [(E)-4-((4-chlorobenzylidene)amino)benezenesulfonamide] and ABEPI2 [N-tert-butyl-2-(1-tert-butyltetrazol-5-yl)sulfanylacetamide], were shown to lead to minocycline accumulation within A. baumannii during serum growth and inhibit the efflux potential of the organism. While both compounds also inhibited the antibiotic efflux properties of the bacterial pathogen Pseudomonas aeruginosa, they did not display significant cytotoxicity toward human cells or mammalian Ca(2+) channel inhibitory effects, suggesting that ABEPI1 and ABEPI2 represent promising structural scaffolds for the development of new classes of bacterial antibiotic efflux pump inhibitors that can be used to potentiate the activities of current and future antibiotics for the therapeutic intervention of Gram-negative bacterial infections.
| S-EPMC4249429 | biostudies-literature