scholarly journals Vaginal Gel Component Hydroxyethyl Cellulose Significantly Enhances the Infectivity ofChlamydia trachomatisSerovars D and E

2018 ◽  
Vol 63 (1) ◽  
Author(s):  
Tímea Raffai ◽  
Katalin Burián ◽  
László Janovák ◽  
Anita Bogdanov ◽  
Johannes H. Hegemann ◽  
...  
Keyword(s):  
Fold Increase ◽  
Hydroxyethyl Cellulose ◽  
Gelling Agent ◽  
Maximal Increase ◽  
Content Type ◽  
Enhancing Effect ◽  
Vaginal Gels ◽  
Dependent Growth

ABSTRACTThe transmission of the urogenital serovars ofChlamydia trachomatiscan be significantly influenced by vaginal gels. Hydroxyethyl cellulose is a commonly used gelling agent that can be found in vaginal gels. Hydroxyethyl cellulose showed a concentration-dependent growth-enhancing effect onC. trachomatisserovars D and E, with a 26.1-fold maximal increasein vitroand a 2.57-fold increasein vivo.

scholarly journals Albumin Enhances Caspofungin Activity against Aspergillus Species by Facilitating Drug Delivery to Germinating Hyphae

2015 ◽  
Vol 60 (3) ◽  
pp. 1226-1233 ◽  
Author(s):  
Petros Ioannou ◽  
Aggeliki Andrianaki ◽  
Tonia Akoumianaki ◽  
Irene Kyrmizi ◽  
Nathaniel Albert ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Cell Culture ◽  
Antifungal Agents ◽  
Fold Increase ◽  
Culture Conditions ◽  
The Other ◽  
Related Factors ◽  
Content Type

The modestin vitroactivity of echinocandins againstAspergillusimplies that host-related factors augment the action of these antifungal agentsin vivo. We found that, in contrast to the other antifungal agents (voriconazole, amphotericin B) tested, caspofungin exhibited a profound increase in activity against variousAspergillusspecies under conditions of cell culture growth, as evidenced by a ≥4-fold decrease in minimum effective concentrations (MECs) (P= 0. 0005). Importantly, the enhanced activity of caspofungin againstAspergillusspp. under cell culture conditions was strictly dependent on serum albumin and was not observed with the other two echinocandins, micafungin and anidulafungin. Of interest, fluorescently labeled albumin bound preferentially on the surface of germinatingAspergillushyphae, and this interaction was further enhanced upon treatment with caspofungin. In addition, supplementation of cell culture medium with albumin resulted in a significant, 5-fold increase in association of fluorescently labeled caspofungin withAspergillushyphae (P< 0.0001). Collectively, we found a novel synergistic interaction between albumin and caspofungin, with albumin acting as a potential carrier molecule to facilitate antifungal drug delivery toAspergillushyphae.

scholarly journals Candida albicans Quorum Sensing Molecules Stimulate Mouse Macrophage Migration

2015 ◽  
Vol 83 (10) ◽  
pp. 3857-3864 ◽  
Author(s):  
Jessica C. Hargarten ◽  
Tyler C. Moore ◽  
Thomas M. Petro ◽  
Kenneth W. Nickerson ◽  
Audrey L. Atkin
Keyword(s):  
Candida Albicans ◽  
Fungal Pathogens ◽  
Physiological Mechanism ◽  
Fold Increase ◽  
Immune Recognition ◽  
Macrophage Migration ◽  
Content Type ◽  
Transplant Patients

The polymorphic commensal fungusCandida albicanscauses life-threatening disease via bloodstream and intra-abdominal infections in immunocompromised and transplant patients. Although host immune evasion is a common strategy used by successful human fungal pathogens,C. albicansprovokes recognition by host immune cells less capable of destroying it. To accomplish this,C. albicanswhite cells secrete a low-molecular-weight chemoattractive stimulant(s) of macrophages, a phagocyte that they are able to survive within and eventually escape from.C. albicansopaque cells do not secrete this chemoattractive stimulant(s). We report here a physiological mechanism that contributes to the differences in the interaction ofC. albicanswhite and opaque cells with macrophages.E,E-Farnesol, which is secreted by white cells only, is a potent stimulator of macrophage chemokinesis, whose activity is enhanced by yeast cell wall components and aromatic alcohols.E,E-farnesol results in up to an 8.5-fold increase in macrophage migrationin vitroand promotes a 3-fold increase in the peritoneal infiltration of macrophagesin vivo. Therefore, modulation of farnesol secretion to stimulate host immune recognition by macrophages may help explain why this commensal is such a successful pathogen.

scholarly journals Click Chemistry-Facilitated Structural Diversification of Nitrothiazoles, Nitrofurans, and Nitropyrroles Enhances Antimicrobial Activity against Giardia lamblia

2017 ◽  
Vol 61 (6) ◽  
Author(s):  
Wan Jung Kim ◽  
Keith A. Korthals ◽  
Suhua Li ◽  
Christine Le ◽  
Jarosław Kalisiak ◽  
...  
Keyword(s):  
Click Chemistry ◽  
Giardia Lamblia ◽  
Diarrheal Disease ◽  
Wide Spectrum ◽  
Fold Increase ◽  
Side Chain ◽  
Full Potential ◽  
Content Type

ABSTRACT Giardia lamblia is an important and ubiquitous cause of diarrheal disease. The primary agents in the treatment of giardiasis are nitroheterocyclic drugs, particularly the imidazoles metronidazole and tinidazole and the thiazole nitazoxanide. Although these drugs are generally effective, treatment failures occur in up to 20% of cases, and resistance has been demonstrated in vivo and in vitro. Prior work had suggested that side chain modifications of the imidazole core can lead to new effective 5-nitroimidazole drugs that can combat nitro drug resistance, but the full potential of nitroheterocycles other than imidazole to yield effective new antigiardial agents has not been explored. Here, we generated derivatives of two clinically utilized nitroheterocycles, nitrothiazole and nitrofuran, as well as a third heterocycle, nitropyrrole, which is related to nitroimidazole but has not been systematically investigated as an antimicrobial drug scaffold. Click chemistry was employed to synthesize 442 novel nitroheterocyclic compounds with extensive side chain modifications. Screening of this library against representative G. lamblia strains showed a wide spectrum of in vitro activities, with many of the compounds exhibiting superior activity relative to reference drugs and several showing >100-fold increase in potency and the ability to overcome existing forms of metronidazole resistance. The majority of new compounds displayed no cytotoxicity against human cells, and several compounds were orally active against murine giardiasis in vivo. These findings provide additional impetus for the systematic development of nitroheterocyclic compounds with nonimidazole cores as alternative and improved agents for the treatment of giardiasis and potentially other infectious agents.

scholarly journals Cryptococcal Phospholipase B1 Is Required for Intracellular Proliferation and Control of Titan Cell Morphology during Macrophage Infection

2015 ◽  
Vol 83 (4) ◽  
pp. 1296-1304 ◽  
Author(s):  
Robert J. Evans ◽  
Zhongming Li ◽  
William S. Hughes ◽  
Julianne T. Djordjevic ◽  
Kirsten Nielsen ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Virulence Factors ◽  
Fold Increase ◽  
Macrophage Infection ◽  
Content Type ◽  
The Central Nervous System ◽  
Opportunistic Fungal Pathogen ◽  
And Control

Cryptococcus neoformansis an opportunistic fungal pathogen and a leading cause of fungal-infection-related fatalities, especially in immunocompromised hosts. Several virulence factors are known to play a major role in the pathogenesis of cryptococcal infections, including the enzyme phospholipase B1 (Plb1). Compared to other well-studiedCryptococcus neoformansvirulence factors such as the polysaccharide capsule and melanin production, very little is known about the contribution of Plb1 to cryptococcal virulence. Phospholipase B1 is a phospholipid-modifying enzyme that has been implicated in multiple stages of cryptococcal pathogenesis, including initiation and persistence of pulmonary infection and dissemination to the central nervous system, but the underlying reason for these phenotypes remains unknown. Here we demonstrate that a Δplb1knockout strain ofC. neoformanshas a profound defect in intracellular growth within host macrophages. This defect is due to a combination of a 50% decrease in proliferation and a 2-fold increase in cryptococcal killing within the phagosome. In addition, we show for the first time that the Δplb1strain undergoes a morphological change duringin vitroandin vivointracellular infection, resulting in a subpopulation of very large titan cells, which may arise as a result of the attenuated mutant's inability to cope within the macrophage.

scholarly journals The Efflux Pump Inhibitor Timcodar Improves the Potency of Antimycobacterial Agents

2014 ◽  
Vol 59 (3) ◽  
pp. 1534-1541 ◽  
Author(s):  
Trudy H. Grossman ◽  
Carolyn M. Shoen ◽  
Steven M. Jones ◽  
Peter L. Jones ◽  
Michael H. Cynamon ◽  
...  
Keyword(s):  
Mouse Model ◽  
Efflux Pump ◽  
Fold Increase ◽  
Broth Culture ◽  
Efflux Pump Inhibitor ◽  
Content Type ◽  
Combination Studies ◽  
Drug Dependent

ABSTRACTPrevious studies indicated that inhibition of efflux pumps augments tuberculosis therapy. In this study, we used timcodar (formerly VX-853) to determine if this efflux pump inhibitor could increase the potency of antituberculosis (anti-TB) drugs againstMycobacterium tuberculosisinin vitroandin vivocombination studies. When used alone, timcodar weakly inhibitedM. tuberculosisgrowth in broth culture (MIC, 19 μg/ml); however, it demonstrated synergism in drug combination studies with rifampin, bedaquiline, and clofazimine but not with other anti-TB agents. WhenM. tuberculosiswas cultured in host macrophage cells, timcodar had about a 10-fold increase (50% inhibitory concentration, 1.9 μg/ml) in the growth inhibition ofM. tuberculosisand demonstrated synergy with rifampin, moxifloxacin, and bedaquiline. In a mouse model of tuberculosis lung infection, timcodar potentiated the efficacies of rifampin and isoniazid, conferring 1.0 and 0.4 log10reductions in bacterial burden in lung, respectively, compared to the efficacy of each drug alone. Furthermore, timcodar reduced the likelihood of a relapse infection when evaluated in a mouse model of long-term, chronic infection with treatment with a combination of rifampin, isoniazid, and timcodar. Although timcodar had no effect on the pharmacokinetics of rifampin in plasma and lung, it did increase the plasma exposure of bedaquiline. These data suggest that the antimycobacterial drug-potentiating activity of timcodar is complex and drug dependent and involves both bacterial and host-targeted mechanisms. Further study of the improvement of the potency of antimycobacterial drugs and drug candidates when used in combination with timcodar is warranted.

scholarly journals Pneumocystis Infection in an Immunocompetent Host Can Promote Collateral Sensitization to Respiratory Antigens

2011 ◽  
Vol 79 (5) ◽  
pp. 1905-1914 ◽  
Author(s):  
Steve D. Swain ◽  
Nicole Meissner ◽  
Soo Han ◽  
Allen Harmsen
Keyword(s):  
Pulmonary Inflammation ◽  
Fold Increase ◽  
Airway Disease ◽  
Interleukin 4 ◽  
Content Type ◽  
Exogenous Antigen ◽  
Opportunistic Fungal Pathogen ◽  
Pneumocystis Infection

ABSTRACTInfection with the opportunistic fungal pathogenPneumocystisis assumed to pass without persistent pathology in immunocompetent hosts. However, when immunocompetent BALB/c mice were inoculated withPneumocystis, a vigorous Th2-like pulmonary inflammation ensued and peaked at 14 days postinfection. This coincided with a 10-fold increase in the number of antigen-presenting cells (APCs) in the lung, and these cells were capable of presenting antigenin vitro, as well as greater uptake of antigenin vivo. When mice were presented with exogenous antigen at the 14-day time point of the infection, they developed respiratory sensitization to that antigen, in the form of increased airway hyperresponsiveness upon a later challenge, whereas mice not infected but presented with antigen did not. Like other forms of collateral sensitization, this response was dependent on interleukin-4 receptor signaling. This ability to facilitate sensitization to exogenous antigen has been previously reported for other infectious disease agents; however,Pneumocystisappears to be uniquely capable in this respect, as a single intranasal dose without added adjuvant, when it was administered at the appropriate time, was sufficient to initiate sensitization.Pneumocystisinfection probably occurs in most humans during the first few years of life, and in the vast majority of cases, it fails to cause any overt direct pathology. However, as we show here,Pneumocystiscan be an agent of comorbidity at this time by facilitating respiratory sensitization that may relate to the later development or exacerbation of obstructive airway disease.

scholarly journals Characterizing the Antimicrobial Activity of N2,N4-Disubstituted Quinazoline-2,4-Diamines toward Multidrug-Resistant Acinetobacter baumannii

2017 ◽  
Vol 61 (6) ◽  
Author(s):  
Renee Fleeman ◽  
Kurt S. Van Horn ◽  
Megan M. Barber ◽  
Whittney N. Burda ◽  
David L. Flanigan ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Acinetobacter Baumannii ◽  
Alkyl Substituent ◽  
Fold Increase ◽  
Multidrug Resistant ◽  
Antibiofilm Activity ◽  
Gram Negative ◽  
Content Type

ABSTRACT We previously reported a series of N 2,N 4-disubstituted quinazoline-2,4-diamines as dihydrofolate reductase inhibitors with potent in vitro and in vivo antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) strains. In this work, we extended our previous study to the Gram-negative pathogen Acinetobacter baumannii. We determined that optimized N 2,N 4-disubstituted quinazoline-2,4-diamines are strongly antibacterial against multidrug-resistant A. baumannii strains when the 6-position is replaced with a halide or an alkyl substituent. Such agents display potent antibacterial activity, with MICs as low as 0.5 μM, while proving to be strongly bactericidal. Interestingly, these compounds also possess the potential for antibiofilm activity, eradicating 90% of cells within a biofilm at or near MICs. Using serial passage assays, we observed a limited capacity for the development of resistance toward these molecules (4-fold increase in MIC) compared to existing folic acid synthesis inhibitors, such as trimethoprim (64-fold increase) and sulfamethoxazole (128-fold increase). We also identified limited toxicity toward human cells, with 50% lethal doses (LD50s) of ≤23 μM for lead agents 4 and 5. Finally, we demonstrated that our lead agents have excellent in vivo efficacy, with lead agent 5 proving more efficacious than tigecycline in a murine model of A. baumannii infection (90% survival versus 66%), despite being used at a lower dose (2 versus 30 mg kg−1). Together, our results demonstrate that N 2,N 4-disubstituted quinazoline-2,4-diamines have strong antimicrobial and antibiofilm activities against both Gram-positive organisms and Gram-negative pathogens, suggesting strong potential for their development as antibacterial agents.

scholarly journals Mycobacterium tuberculosis embBCodon 306 Mutations Confer Moderately Increased Resistance to Ethambutol In Vitro and In Vivo

2011 ◽  
Vol 55 (6) ◽  
pp. 2891-2896 ◽  
Author(s):  
Claudia Plinke ◽  
Kerstin Walter ◽  
Sahar Aly ◽  
Stefan Ehlers ◽  
Stefan Niemann
Keyword(s):  
Resistance Mechanism ◽  
Point Mutations ◽  
Fold Increase ◽  
Wild Type ◽  
Content Type ◽  
First Line Therapy ◽  
The One ◽  
The Impact

ABSTRACTEthambutol (EMB) is a major component of the first-line therapy of tuberculosis. Mutations in codon 306 ofembB(embB306) were suggested as a major resistance mechanism in clinical isolates. To directly analyze the impact of individualembB306 mutations on EMB resistance, we used allelic exchange experiments to generateembB306 mutants ofM. tuberculosisH37Rv. The level of EMB resistance conferred by particular mutations was measuredin vitroandin vivoafter EMB therapy by daily gavage in a mouse model of aerogenic tuberculosis. The wild-typeembB306 ATG codon was replaced byembB306 ATC, ATA, or GTG, respectively. All of the obtainedembB306 mutants exhibited a 2- to 4-fold increase in EMB MIC compared to the wild-type H37Rv.In vivo, the one selectedembB306 GTG mutant required a higher dose of ethambutol to restrict its growth in the lung compared to wild-type H37Rv. These experiments demonstrate thatembB306 point mutations enhance the EMB MICin vitroto a moderate, but significant extent, and reduce the efficacy of EMB treatment in the animal model. We propose that conventional EMB susceptibility testing, in combination withembB306 genotyping, may guide dose adjustment to avoid clinical treatment failure in these low-level resistant strains.

scholarly journals FORMULATION AND IN VITRO, IN VIVO EVALUATION OF PRONIOSOMAL GEL OF NEOMYCIN SULPHATE

2019 ◽  
pp. 156-163
Author(s):  
AMOL SHETE ◽  
PRIYANKA THORAT ◽  
RAJENDRA DOIJAD ◽  
SACHIN SAJANE
Keyword(s):  
Phase Separation ◽  
Skin Irritation ◽  
Entrapment Efficiency ◽  
Separation Method ◽  
Gelling Agent ◽  
In Vivo Evaluation ◽  
Skin Delivery ◽  
Span 60

Objective: The objectives of present investigation were to prepare and evaluate proniosomes of neomycin sulphate (NS) by coacervation phase separation method by using sorbitan monostearate (span 60) and lecithin as a surfactant to increase the penetration through the skin and study the effect of concentration of the same. Methods: Proniosomes of neomycin sulphate (NS) were prepared by coacervation phase separation method by using span 60 and lecithin. The effect of concentration of span 60 and lecithin was studied by factorial design. The prepared proniosomes were converted to gel by using carbopol as a gelling agent. The prepared formulations were evaluated for entrapment efficiency, in vitro drug diffusion, in vitro antibacterial activity and in vivo skin irritation test etc. Results: All Formulation showed the percentage entrapment efficiency in the range 38.31±0.05% to 77.96±0.06%, good homogeneity and gel was easily spreadable with minimal of shear. Optimized formulation showed enhanced rate of diffusion in vitro, increase in zone of inhibition against staphylococcus aureus, no skin irritation and showed good stability. Conclusion: The results of present study indicates that proniosomal gel formulated by using combination of span 60, Lecithin, cholesterol can be used to enhance skin delivery of NS because of excellent permeation of drug. Developed proniosomal gel formulation was promising carrier for NS

scholarly journals Methylation of rRNA as a host defense against rampant group II intron retrotransposition

Mobile DNA ◽  
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Justin M. Waldern ◽  
Dorie Smith ◽  
Carol Lyn Piazza ◽  
E. Jake Bailey ◽  
Nicholas J. Schiraldi ◽  
...  
Keyword(s):  
Insertional Mutagenesis ◽  
Fold Increase ◽  
Group Ii Intron ◽  
In Vivo Experiments ◽  
Cellular Factors ◽  
Group Ii ◽  
Self Splicing ◽  
Native Host

Abstract Background Group II introns are mobile retroelements, capable of invading new sites in DNA. They are self-splicing ribozymes that complex with an intron-encoded protein to form a ribonucleoprotein that targets DNA after splicing. These molecules can invade DNA site-specifically, through a process known as retrohoming, or can invade ectopic sites through retrotransposition. Retrotransposition, in particular, can be strongly influenced by both environmental and cellular factors. Results To investigate host factors that influence retrotransposition, we performed random insertional mutagenesis using the ISS1 transposon to generate a library of over 1000 mutants in Lactococcus lactis, the native host of the Ll.LtrB group II intron. By screening this library, we identified 92 mutants with increased retrotransposition frequencies (RTP-ups). We found that mutations in amino acid transport and metabolism tended to have increased retrotransposition frequencies. We further explored a subset of these RTP-up mutants, the most striking of which is a mutant in the ribosomal RNA methyltransferase rlmH, which exhibited a reproducible 20-fold increase in retrotransposition frequency. In vitro and in vivo experiments revealed that ribosomes in the rlmH mutant were defective in the m3Ψ modification and exhibited reduced binding to the intron RNA. Conclusions Taken together, our results reinforce the importance of the native host organism in regulating group II intron retrotransposition. In particular, the evidence from the rlmH mutant suggests a role for ribosome modification in limiting rampant retrotransposition.

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