scholarly journals Curcumin Analogues as a Potential Drug against Antibiotic Resistant Protein, β-Lactamases and L, D-Transpeptidases Involved in Toxin Secretion in Salmonella typhi: A Computational Approach

2021 ◽  
Vol 2 (1) ◽  
pp. 77-100
Author(s):  
Tanzina Akter ◽  
Mahim Chakma ◽  
Afsana Yeasmin Tanzina ◽  
Meheadi Hasan Rumi ◽  
Mst. Sharmin Sultana Shimu ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Typhoid Fever ◽  
Homology Modeling ◽  
Salmonella Typhi ◽  
Multidrug Resistant ◽  
Drug Candidate ◽  
In Vivo Experiments ◽  
Curcumin Analogs

Typhoid fever caused by the bacteria Salmonella typhi gained resistance through multidrug-resistant S. typhi strains. One of the reasons behind β-lactam antibiotic resistance is -lactamase. L, D-Transpeptidases is responsible for typhoid fever as it is involved in toxin release that results in typhoid fever in humans. A molecular modeling study of these targeted proteins was carried out by various methods, such as homology modeling, active site prediction, prediction of disease-causing regions, and by analyzing the potential inhibitory activities of curcumin analogs by targeting these proteins to overcome the antibiotic resistance. The five potent drug candidate compounds were identified to be natural ligands that can inhibit those enzymes compared to controls in our research. The binding affinity of both the Go-Y032 and NSC-43319 were found against β-lactamase was −7.8 Kcal/mol in AutoDock, whereas, in SwissDock, the binding energy was −8.15 and −8.04 Kcal/mol, respectively. On the other hand, the Cyclovalone and NSC-43319 had an equal energy of −7.60 Kcal/mol in AutoDock, whereas −7.90 and −8.01 Kcal/mol in SwissDock against L, D-Transpeptidases. After the identification of proteins, the determination of primary and secondary structures, as well as the gene producing area and homology modeling, was accomplished. The screened drug candidates were further evaluated in ADMET, and pharmacological properties along with positive drug-likeness properties were observed for these ligand molecules. However, further in vitro and in vivo experiments are required to validate these in silico data to develop novel therapeutics against antibiotic resistance.

Transfer of antibiotic resistance determinants between lactobacilli isolates from the gastrointestinal tract of chicken

2012 ◽  
Vol 3 (2) ◽  
pp. 137-144 ◽  
Author(s):  
F. Vieira de Souza ◽  
R. Roque ◽  
J.L. Silva Moreira ◽  
M. Resende de Souza ◽  
J.R. Nicoli ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Gastrointestinal Tract ◽  
Broiler Chickens ◽  
Lactobacillus Reuteri ◽  
Multi Drug Resistance ◽  
Bacterial Strains ◽  
Genetic Traits ◽  
In Vivo Experiments

The aim of this study was to assess the potential horizontal transfer of genetic traits for antibiotic resistance between lactobacilli isolated from the chicken gut, both in vitro and in vivo. Thirty-seven Lactobacillus spp. strains isolated from the gizzard, small and large intestines and caeca of free-range broiler chickens showed multi-drug resistance as assessed by disc diffusion assays. The minimum inhibitory concentration (MIC) for vancomycin, tetracycline, erythromycin and chloramphenicol was determined in De Man, Rogosa and Sharpe broth in a microplate assay. Almost all the lactobacilli isolates were resistant to vancomycin (except strains belonging to the Lactobacillus acidophilus group) and to tetracycline (MIC≥128 μg/ml). Only five strains were resistant to erythromycin, and six to chloramphenicol. The transfer rate in filter mating experiments performed using L. acidophilus strain 4M14E (EmR), Lactobacillus vaginalis strain 5M14E (CmR), Lactobacillus salivarius strain 5C14C (EmR), and the 4G14L and 3C14C strains of Lactobacillus reuteri (CmR) showed a frequency of approximately 1×104 cfu/ml of double-resistant transconjugants for the different combinations. The exception was the L. salivarius 5C14C (EmR) and L. vaginalis 5M14E (CmR) mating combination, which produced no transconjugants. In vivo experiments performed in gnotobiotic mice by mating L. acidophilus 4M14E (EmR) with L. reuteri 3C14C (CmR), L. reuteri 4G14L (CmR) or L. vaginalis 5M14E (CmR) resulted in transconjugants at 3.95±0.29, 3.16±0.33, and 4.55±1.52 log10 cfu/g of faeces, respectively. Taken together, these data suggest that genetic exchange may occur between native bacterial strains within the gastrointestinal tract of chickens, which might maintain a dynamic gene pool conferring antibiotic resistance upon indigenous microbiota components, even in the absence of the pathogens. This possibility must be taken into account as a complementary criterion when lactobacilli are screened for probiotic use.

scholarly journals Is there any association between antibiotic resistance and virulence genes in Enterococcus isolates?

2019 ◽  
Vol 6 (12) ◽  
pp. 310-315
Author(s):  
Nergis Aşgın ◽  
Emre Taşkın
Keyword(s):  
Antibiotic Resistance ◽  
Virulence Genes ◽  
Multidrug Resistant ◽  
Automated System ◽  
High Frequencies ◽  
Resistant Strains ◽  
Vancomycin Resistant ◽  
High Level

Objective: In this study, we aim to determine the frequency of antibiotic resistance and five virulence genes in Enterococcus species and the relationship between antibiotic resistance and virulence genes. Material and Methods: A total of 86 Enterococcus strains isolated from inpatients between 2015 and 2016 were included. Identification and antibiotic susceptibilities of strains were determined using a BD Phoenix fully automated system. The presence of virulence-associated genes (esp, gel E, asa1, hyl, and cyl) were investigated by using PCR method. Results: Of the 86 Enterococcus strains, 53 (61.6%) and 33 (38.4%) were Enterococcus faecium and Enterococcus faecalis, respectively. Vancomycin and high-level gentamicin resistance (HLGR) in E. faecalis strains were 0.6% and 60.6%, respectively. Furthermore, 52 of the 53 E. faecium strains were both vancomycin-resistant and HLGR. The frequency of esp, gel E, asa1, cyl, and hyl was 91.9%, 60.5%, 54.7%, 43%, and 26.7%, respectively.  The asa 1, cyl, and gel E genes were detected at high frequencies in vancomycin-susceptible and non-HLGR strains, whereas hyl gene was detected at high frequencies in vancomycin-resistant and HLGR strains. Conclusion: Virulence genes were more frequent in vancomycin-susceptible and non-HLGR Enterococcus strains than in the resistant strains. Although infections caused by multidrug-resistant strains are difficult to treat, it should be considered that susceptible strains have more virulence genes. This may reduce the in vivo efficacy of drugs and lead to treatment failures. Therefore, in addition to the in vitro susceptibilities of drugs, clinical efficacy should be monitored.

scholarly journals 1,4-Azaindole, a Potential Drug Candidate for Treatment of Tuberculosis

2014 ◽  
Vol 58 (9) ◽  
pp. 5325-5331 ◽  
Author(s):  
Monalisa Chatterji ◽  
Radha Shandil ◽  
M. R. Manjunatha ◽  
Suresh Solapure ◽  
Vasanthi Ramachandran ◽  
...  
Keyword(s):  
Antitubercular Activity ◽  
Multidrug Resistant ◽  
Antagonistic Activity ◽  
Drug Candidate ◽  
Content Type ◽  
Human Dose ◽  
Safety Risks ◽  
Infection Models

ABSTRACTNew therapeutic strategies against multidrug-resistant (MDR) and extensively drug-resistant (XDR)Mycobacterium tuberculosisare urgently required to combat the global tuberculosis (TB) threat. Toward this end, we previously reported the identification of 1,4-azaindoles, a promising class of compounds with potent antitubercular activity through noncovalent inhibition of decaprenylphosphoryl-β-d-ribose 2′-epimerase (DprE1). Further, this series was optimized to improve its physicochemical properties and pharmacokinetics in mice. Here, we describe the short-listing of a potential clinical candidate, compound 2, that has potent cellular activity, drug-like properties, efficacy in mouse and rat chronic TB infection models, and minimalin vitrosafety risks. We also demonstrate that the compounds, including compound 2, have no antagonistic activity with other anti-TB drugs. Moreover, compound 2 shows synergy with PA824 and TMC207in vitro, and the synergy effect is translatedin vivowith TMC207. The series is predicted to have a low clearance in humans, and the predicted human dose for compound 2 is ≤1 g/day. Altogether, our data suggest that a 1,4-azaindole (compound 2) is a promising candidate for the development of a novel anti-TB drug.

scholarly journals Ferrocifen Loaded Lipid Nanocapsules: A Promising Anticancer Medication against Multidrug Resistant Tumors

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2291
Author(s):  
Pierre Idlas ◽  
Elise Lepeltier ◽  
Gérard Jaouen ◽  
Catherine Passirani
Keyword(s):  
Cancer Cells ◽  
Organometallic Compounds ◽  
Multidrug Resistant ◽  
Quinone Methide ◽  
Chemotherapeutic Drugs ◽  
Lipid Nanocapsules ◽  
In Vivo Experiments ◽  
Hydrophobic Compounds

Resistance of cancer cells to current chemotherapeutic drugs has obliged the scientific community to seek innovative compounds. Ferrocifens, lipophilic organometallic compounds composed of a tamoxifen scaffold covalently bound to a ferrocene moiety, have shown very interesting antiproliferative, cytotoxic and immunologic effects. The formation of ferrocenyl quinone methide plays a crucial role in the multifaceted activity of ferrocifens. Lipid nanocapsules (LNCs), meanwhile, are nanoparticles obtained by a free organic solvent process. LNCs consist of an oily core surrounded by amphiphilic surfactants and are perfectly adapted to encapsulate these hydrophobic compounds. The different in vitro and in vivo experiments performed with this ferrocifen-loaded nanocarrier have revealed promising results in several multidrug-resistant cancer cell lines such as glioblastoma, breast cancer and metastatic melanoma, alone or in combination with other therapies. This review provides an exhaustive summary of the use of ferrocifen-loaded LNCs as a promising nanomedicine, outlining the ferrocifen mechanisms of action on cancer cells, the nanocarrier formulation process and the in vivo results obtained over the last two decades.

scholarly journals Inhibition of Pseudomonas aeruginosa by Peptide-Conjugated Phosphorodiamidate Morpholino Oligomers

2017 ◽  
Vol 61 (4) ◽  
Author(s):  
James J. Howard ◽  
Carolyn R. Sturge ◽  
Dina A. Moustafa ◽  
Seth M. Daly ◽  
Kimberly R. Marshall-Batty ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antibiotic Resistance ◽  
Polymyxin B ◽  
Multidrug Resistant ◽  
Essential Genes ◽  
Content Type ◽  
Novel Approach ◽  
Phosphorodiamidate Morpholino Oligomers

ABSTRACT Pseudomonas aeruginosa is a highly virulent, multidrug-resistant pathogen that causes significant morbidity and mortality in hospitalized patients and is particularly devastating in patients with cystic fibrosis. Increasing antibiotic resistance coupled with decreasing numbers of antibiotics in the developmental pipeline demands novel antibacterial approaches. Here, we tested peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs), which inhibit translation of complementary mRNA from specific, essential genes in P. aeruginosa. PPMOs targeted to acpP, lpxC, and rpsJ, inhibited P. aeruginosa growth in many clinical strains and activity of PPMOs could be enhanced 2- to 8-fold by the addition of polymyxin B nonapeptide at subinhibitory concentrations. The PPMO targeting acpP was also effective at preventing P. aeruginosa PAO1 biofilm formation and at reducing existing biofilms. Importantly, treatment with various combinations of a PPMO and a traditional antibiotic demonstrated synergistic growth inhibition, the most effective of which was the PPMO targeting rpsJ with tobramycin. Furthermore, treatment of P. aeruginosa PA103-infected mice with PPMOs targeting acpP, lpxC, or rpsJ significantly reduced the bacterial burden in the lungs at 24 h by almost 3 logs. Altogether, this study demonstrates that PPMOs targeting the essential genes acpP, lpxC, or rpsJ in P. aeruginosa are highly effective at inhibiting growth in vitro and in vivo. These data suggest that PPMOs alone or in combination with antibiotics represent a novel approach to addressing the problems associated with rapidly increasing antibiotic resistance in P. aeruginosa.

scholarly journals Conjugative Delivery of CRISPR-Cas9 for the Selective Depletion of Antibiotic-Resistant Enterococci

2019 ◽  
Vol 63 (11) ◽  
Author(s):  
Marinelle Rodrigues ◽  
Sara W. McBride ◽  
Karthik Hullahalli ◽  
Kelli L. Palmer ◽  
Breck A. Duerkop
Keyword(s):  
Antibiotic Resistance ◽  
Bacterial Infections ◽  
Antibiotic Resistance Genes ◽  
Multidrug Resistant ◽  
Conjugative Plasmid ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Resistance Determinants

ABSTRACT The innovation of new therapies to combat multidrug-resistant (MDR) bacteria is being outpaced by the continued rise of MDR bacterial infections. Of particular concern are hospital-acquired infections (HAIs) that are recalcitrant to antibiotic therapies. The Gram-positive intestinal pathobiont Enterococcus faecalis is associated with HAIs, and some strains are MDR. Therefore, novel strategies to control E. faecalis populations are needed. We previously characterized an E. faecalis type II CRISPR-Cas system and demonstrated its utility in the sequence-specific removal of antibiotic resistance determinants. Here, we present work describing the adaption of this CRISPR-Cas system into a constitutively expressed module encoded on a pheromone-responsive conjugative plasmid that efficiently transfers to E. faecalis for the selective removal of antibiotic resistance genes. Using in vitro competition assays, we show that these CRISPR-Cas-encoding delivery plasmids, or CRISPR-Cas antimicrobials, can reduce the occurrence of antibiotic resistance in enterococcal populations in a sequence-specific manner. Furthermore, we demonstrate that deployment of CRISPR-Cas antimicrobials in the murine intestine reduces the occurrence of antibiotic-resistant E. faecalis by several orders of magnitude. Finally, we show that E. faecalis donor strains harboring CRISPR-Cas antimicrobials are immune to uptake of antibiotic resistance determinants in vivo. Our results demonstrate that conjugative delivery of CRISPR-Cas antimicrobials may be adaptable for future deployment from probiotic bacteria for exact targeting of defined MDR bacteria or for precision engineering of polymicrobial communities in the mammalian intestine.

scholarly journals Acetyleugenol from Acacia nilotica (L.) exhibits a strong antibacterial activity and its phenyl and indole analogs show a promising anti-TB potential

2020 ◽  
Author(s):  
Abubakar Abdulhamid ◽  
Talal Adlan ◽  
Abdalla Ahmed ◽  
Faisal Koua ◽  
Amar Ismail
Keyword(s):  
Drug Targets ◽  
Salmonella Typhi ◽  
Acacia Nilotica ◽  
Zone Of Inhibition ◽  
Streptococcus Pneumonia ◽  
In Vivo Experiments ◽  
First Time ◽  
Antibacterial Potential

Acetyleugenol is a phytochemical compound with broad effect against infectious diseases and tumors. Here, we extracted, characterized and elucidated the structure of acetyeugenol, for the first time, from the leaves of Acacia nilotica (L.)―a well-known medicinal plant. The broad antibacterial potential of acetyleugenol was first confirmed against seven bacterial pathogenic isolates with best activity against Proteus sp., Salmonella typhi, Staphylococcu aureus, and Streptococcus pneumonia, which showed similar or better zone of inhibition to that of the control amoxicillin. To further investigate its effect against Mycobacterium tuberculosis, acetyleugenol and its indole and phenyl analogs were subjected to molecular docking experiments against two potential tuberculosis drug targets―MtPknE and MtPknB Ser/Thr protein kinases. The results reveal that all of the analogs have improved docking scores comparing to the acetyleugenol. The indole analogs EUG-1 and EUG-3 were more effective with better docking scores for MtPknE with –11.08 and –10.05 kcal/mol, respectively. Similar results were obtained for the MtPknB. In contrast, only the EUG-2 phenyl analog has given rise to similar docking scores for both targets. This opens the door for further comprehensive studies on these acetyleugenol analogs with in vitro and in vivo experiments to validate and get more insights into their mechanisms of action.

scholarly journals Phosphate-Containing Polyethylene Glycol Polymers Prevent Lethal Sepsis by Multidrug-Resistant Pathogens

2013 ◽  
Vol 58 (2) ◽  
pp. 966-977 ◽  
Author(s):  
Alexander Zaborin ◽  
Jennifer R. Defazio ◽  
Matthew Kade ◽  
Brooke L. Deatherage Kaiser ◽  
Natalia Belogortseva ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Polyethylene Glycol ◽  
Animal Studies ◽  
Multidrug Resistant ◽  
Core Microbiome ◽  
High Molecular Weight Polymer ◽  
Molecular Weight Polymer ◽  
Bacteria And Fungi

ABSTRACTAntibiotic resistance among highly pathogenic strains of bacteria and fungi is a growing concern in the face of the ability to sustain life during critical illness with advancing medical interventions. The longer patients remain critically ill, the more likely they are to become colonized by multidrug-resistant (MDR) pathogens. The human gastrointestinal tract is the primary site of colonization of many MDR pathogens and is a major source of life-threatening infections due to these microorganisms. Eradication measures to sterilize the gut are difficult if not impossible and carry the risk of further antibiotic resistance. Here, we present a strategy to contain rather than eliminate MDR pathogens by using an agent that interferes with the ability of colonizing pathogens to express virulence in response to host-derived and local environmental factors. The antivirulence agent is a phosphorylated triblock high-molecular-weight polymer (here termed Pi-PEG 15–20) that exploits the known properties of phosphate (Pi) and polyethylene glycol 15-20 (PEG 15-20) to suppress microbial virulence and protect the integrity of the intestinal epithelium. The compound is nonmicrobiocidal and appears to be highly effective when tested bothin vitroandin vivo. Structure functional analyses suggest that the hydrophobic bis-aromatic moiety at the polymer center is of particular importance to the biological function of Pi-PEG 15-20, beyond its phosphate content. Animal studies demonstrate that Pi-PEG prevents mortality in mice inoculated with multiple highly virulent pathogenic organisms from hospitalized patients in association with preservation of the core microbiome.

scholarly journals Antagonistic Activity ofLactobacillusIsolates againstSalmonella typhi In Vitro

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Amira Abdel-Daim ◽  
Nadia Hassouna ◽  
Mohamed Hafez ◽  
Mohamed Seif Aldeen Ashor ◽  
Mohammad M. Aboulwafa
Keyword(s):  
Typhoid Fever ◽  
Lactobacillus Plantarum ◽  
Antimicrobial Agents ◽  
Salmonella Typhi ◽  
Antagonistic Activity ◽  
Oxygen Tolerance ◽  
Probiotic Potential ◽  
Concurrent Use

Background. Enteric fever is a global health problem, and rapidly developing resistance to various drugs makes the situation more alarming. The potential use ofLactobacillusto control typhoid fever represents a promising approach, as it may exert protective actions through various mechanisms.Methods. In this study, the probiotic potential and antagonistic activities of 32Lactobacillusisolates againstSalmonella typhiwere evaluated. The antimicrobial activity of cell free supernatants ofLactobacillusisolates, interference ofLactobacillusisolates with theSalmonellaadherence and invasion, cytoprotective effect ofLactobacillusisolates, and possibility of concurrent use of testedLactobacillusisolates and antibiotics were evaluated by testing their susceptibilities to antimicrobial agents, and their oxygen tolerance was also examined.Results. The results revealed that twelveLactobacillusisolates could protect againstSalmonella typhiinfection through interference with both its growth and its virulence properties, such as adherence, invasion, and cytotoxicity. TheseLactobacillusisolates exhibited MIC values for ciprofloxacin higher than those ofSalmonella typhiand oxygen tolerance and were identified asLactobacillus plantarum.Conclusion. The testedLactobacillus plantarumisolates can be introduced as potential novel candidates that have to be subjected forin vivoand application studies for treatment and control of typhoid fever.

scholarly journals Discovery of a novel ferroptosis inducer-talaroconvolutin A—killing colorectal cancer cells in vitro and in vivo

2020 ◽  
Vol 11 (11) ◽  
Author(s):  
Yong Xia ◽  
Shuzhi Liu ◽  
Changlin Li ◽  
Zhiying Ai ◽  
Wenzhi Shen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Therapy ◽  
Cancer Cells ◽  
Drug Candidate ◽  
In Vivo Experiments ◽  
Colorectal Cancer Cells ◽  
Liver And Kidney ◽  
Cancer Suppression

AbstractFerropotsis is among the most important mechanisms of cancer suppression, which could be harnessed for cancer therapy. However, no natural small-molecule compounds with cancer inhibitory activity have been identified to date. In the present study, we reported the discovery of a novel ferroptosis inducer, talaroconvolutin A (TalaA), and the underlying molecular mechanism. We discovered that TalaA killed colorectal cancer cells in dose-dependent and time-dependent manners. Interestingly, TalaA did not induce apoptosis, but strongly triggered ferroptosis. Notably, TalaA was significantly more effective than erastin (a well-known ferroptosis inducer) in suppressing colorectal cancer cells via ferroptosis. We revealed a dual mechanism of TalaA’ action against cancer. On the one hand, TalaA considerably increased reactive oxygen species levels to a certain threshold, the exceeding of which induced ferroptosis. On the other hand, this compound downregulated the expression of the channel protein solute carrier family 7 member 11 (SLC7A11) but upregulated arachidonate lipoxygenase 3 (ALOXE3), promoting ferroptosis. Furthermore, in vivo experiments in mice evidenced that TalaA effectively suppressed the growth of xenografted colorectal cancer cells without obvious liver and kidney toxicities. The findings of this study indicated that TalaA could be a new potential powerful drug candidate for colorectal cancer therapy due to its outstanding ability to kill colorectal cancer cells via ferroptosis induction.

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