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 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 Cooperative Role of Antibodies against Heat-Labile Toxin and the EtpA Adhesin in Preventing Toxin Delivery and Intestinal Colonization by Enterotoxigenic Escherichia coli

2012 ◽  
Vol 19 (10) ◽  
pp. 1603-1608 ◽  
Author(s):  
Koushik Roy ◽  
David J. Hamilton ◽  
James M. Fleckenstein
Keyword(s):  
Escherichia Coli ◽  
Diarrheal Disease ◽  
Vaccine Development ◽  
Enterotoxigenic Escherichia Coli ◽  
Intestinal Colonization ◽  
Content Type ◽  
Heat Labile

ABSTRACTEnterotoxigenicEscherichia coli(ETEC) is an important cause of diarrheal disease in developing countries, where it is responsible for hundreds of thousands of deaths each year. Vaccine development for ETEC has been hindered by the heterogeneity of known molecular targets and the lack of broad-based sustained protection afforded by existing vaccine strategies. In an effort to explore the potential role of novel antigens in ETEC vaccines, we examined the ability of antibodies directed against the ETEC heat-labile toxin (LT) and the recently described EtpA adhesin to prevent intestinal colonizationin vivoand toxin delivery to epithelial cellsin vitro. We demonstrate that EtpA is required for the optimal delivery of LT and that antibodies against this adhesin play at least an additive role in preventing delivery of LT to target intestinal cells when combined with antibodies against either the A or B subunits of the toxin. Moreover, vaccination with a combination of LT and EtpA significantly impaired intestinal colonization. Together, these results suggest that the incorporation of recently identified molecules such as EtpA could be used to enhance current approaches to ETEC vaccine development.

scholarly journals Characterization of Intracellular Growth RegulatoricgRby Utilizing Transcriptomics To Identify Mediators of Pathogenesis in Shigella flexneri

2013 ◽  
Vol 81 (9) ◽  
pp. 3068-3076 ◽  
Author(s):  
Carolyn R. Morris ◽  
Christen L. Grassel ◽  
Julia C. Redman ◽  
Jason W. Sahl ◽  
Eileen M. Barry ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Sequencing ◽  
Diarrheal Disease ◽  
Intracellular Growth ◽  
Bioinformatics Analyses ◽  
Content Type ◽  
Regulatory Pathways

ABSTRACTShigellaspecies Gram-negative bacteria which cause a diarrheal disease, known as shigellosis, by invading and destroying the colonic mucosa and inducing a robust inflammatory response. With no vaccine available, shigellosis annually kills over 600,000 children in developing countries. This study demonstrates the utility of combining high-throughput bioinformatic methods within vitroandin vivoassays to provide new insights into pathogenesis. Comparisons ofin vivoandin vitrogene expression identified genes associated with intracellular growth. Additional bioinformatics analyses identified genes that are present inS. flexneriisolates but not in the three otherShigellaspecies. Comparison of these two analyses revealed nine genes that are differentially expressed during invasion and that are specific toS. flexneri. One gene, a DeoR family transcriptional regulator with decreased expression during invasion, was further characterized and is now designatedicgR, forintracellulargrowthregulator. Deletion oficgRcaused no difference in growthin vitrobut resulted in increased intracellular replication in HCT-8 cells. Furtherin vitroandin vivostudies using high-throughput sequencing of RNA transcripts (RNA-seq) of an isogenic ΔicgRmutant identified 34 genes that were upregulated under both growth conditions. This combined informatics and functional approach has allowed the characterization of a gene and pathway previously unknown inShigellapathogenesis and provides a framework for further identification of novel virulence factors and regulatory pathways.

Resistance to Bensulfuron-Methyl in Water Plantain (Alisma plantago-aquatica) Populations from Chilean Paddy Fields

2008 ◽  
Vol 22 (4) ◽  
pp. 602-608 ◽  
Author(s):  
Rodrigo Figueroa ◽  
Marlene Gebauer ◽  
Albert Fischer ◽  
Marcelo Kogan
Keyword(s):  
Weed Management ◽  
Wide Spectrum ◽  
Acetolactate Synthase ◽  
Rice Fields ◽  
Integrated Weed Management ◽  
Cross Resistance ◽  
Content Type ◽  
Als Inhibitors

Bensulfuron-methyl (BSM) has been one of the most widely used herbicides in Chilean rice fields because it controls a wide spectrum of weeds and does not require field drainage for application. However, failures of BSM to control water plantain in rice fields have been noted since 2002. We assessed BSM effects on suspected resistant (CU1 and CU2) and susceptible (AN1) water plantain accessions collected in Chilean rice fields during 2004 and 2005. BSM rates resulting in 50% growth reduction (GR50) of CU2 and CU1 plants were 12- and 33-fold higher than for AN1 plants, respectively. Acetolactate synthase (ALS) activity assays in vitro suggested resistance in CU1 and CU2 was due to an ALS enzyme with reduced BSM sensitivity compared to the AN1 biotype. Resistance indices (RI), or ratios of the resistant to susceptibleI50values (BSM rate to inhibit ALS-enzyme activity by 50%), were 266 (CU2/AN1) and > 38,462 (CU1/AN1). This agreed with in vivo ALS activity assays whereRIwere 224 (CU2/AN1) and > 8,533 (CU1/AN1). Resistance levels detected in whole-plant or in vivo ALS activity assays were orders of magnitude lower than those detected in in vitro ALS activity studies suggesting nontarget site mechanisms may have mitigated BSM toxicity. However, a consistent ranking of BSM sensitivity levels (AN1 > CU2 > CU1) throughout all three types of assays suggests resistance is primarily endowed by low target site sensitivity. We conclude that susceptible and resistant water plantain biotypes coexist in Chilean paddies, and the use of integrated weed management involving herbicides with a different mode of action would be imperative to prevent further evolution of resistance to BSM and possibly cross-resistance to other ALS inhibitors. In vitro ALS-enzyme assays provided the best discrimination of resistance levels between biotypes.

scholarly journals A Reprofiled Drug, Auranofin, Is Effective against Metronidazole-Resistant Giardia lamblia

2013 ◽  
Vol 57 (5) ◽  
pp. 2029-2035 ◽  
Author(s):  
Noa Tejman-Yarden ◽  
Yukiko Miyamoto ◽  
David Leitsch ◽  
Jennifer Santini ◽  
Anjan Debnath ◽  
...  
Keyword(s):  
Protein Function ◽  
Giardia Lamblia ◽  
Diarrheal Disease ◽  
Significant Inhibition ◽  
Chemical Library ◽  
Content Type ◽  
Antigiardial Activity ◽  
Resistant Strains ◽  
Human Use

ABSTRACTGiardiasis is one of the most common causes of diarrheal disease worldwide. Treatment is primarily with 5-nitro antimicrobials, particularly metronidazole. Resistance to metronidazole has been described, and treatment failures can occur in up to 20% of cases, making development of alternative antigiardials an important goal. To this end, we have screened a chemical library of 746 approved human drugs and 164 additional bioactive compounds for activity againstGiardia lamblia. We identified 56 compounds that caused significant inhibition ofG. lambliagrowth and attachment. Of these, 15 were previously reported to have antigiardial activity, 20 were bioactive but not approved for human use, and 21 were drugs approved for human use for other indications. One notable compound of the last group was the antirheumatic drug auranofin. Further testing revealed that auranofin was active in the low (4 to 6)-micromolar range against a range of divergentG. lambliaisolates representing both human-pathogenic assemblages A and B. Most importantly, auranofin was active against multiple metronidazole-resistant strains. Mechanistically, auranofin blocked the activity of giardial thioredoxin oxidoreductase, a critical enzyme involved in maintaining normal protein function and combating oxidative damage, suggesting that this inhibition contributes to the antigiardial activity. Furthermore, auranofin was efficaciousin vivo, as it eradicated infection with differentG. lambliaisolates in different rodent models. These results indicate that the approved human drug auranofin could be developed as a novel agent in the armamentarium of antigiardial drugs, particularly against metronidazole-resistant strains.

scholarly journals Assessment of the In Vivo Activity of SPR741 in Combination with Azithromycin against Multidrug-Resistant Enterobacteriaceae Isolates in the Neutropenic Murine Thigh Infection Model

2018 ◽  
Vol 62 (7) ◽  
Author(s):  
Sean M. Stainton ◽  
Kamilia Abdelraouf ◽  
Luke Utley ◽  
Michael J. Pucci ◽  
Troy Lister ◽  
...  
Keyword(s):  
Potential Role ◽  
Wide Spectrum ◽  
Structural Similarity ◽  
Multidrug Resistant ◽  
Infection Model ◽  
Bacterial Burden ◽  
Content Type ◽  
Novel Agent

ABSTRACT SPR741 is a novel agent with structural similarity to polymyxins that is capable of potentiating the activities of various classes of antibiotics. Previously published studies indicated that although Enterobacteriaceae isolates had minimal susceptibilities to azithromycin (AZM), the in vitro antimicrobial activity of AZM against Enterobacteriaceae was enhanced when it was combined with SPR741. The current study evaluated the in vivo activity of human-simulated regimens (HSR) of AZM equivalent to clinical doses of 500 mg given intravenously (i.v.) every 24 h (q24h) and SPR741 equivalent to clinical doses of 400 mg q8h i.v. (1-h infusion), alone and in combination, against multidrug-resistant (MDR) Enterobacteriaceae . We studied 30 MDR Enterobacteriaceae isolates expressing a wide spectrum of β-lactamases (ESBL, NDM, VIM, and KPC), including a subset of isolates positive for genes conferring macrolide resistance ( mphA , mphE , ermB , and msr ). In vivo activity was assessed as the change in log 10 CFU per thigh at 24 h compared with 0 h. Treatment with AZM alone was associated with net growth of 2.60 ± 0.83 log 10 CFU/thigh. Among isolates with AZM MICs of ≤16 mg/liter, treatment with AZM-SPR741was associated with an average reduction in bacterial burden of −0.53 ± 0.82 log 10 CFU/thigh, and stasis to 1-log kill was observed in 9/11 isolates (81.8%). Combination therapy with an AZM-SPR741 HSR showed promising in vivo activity against MDR Enterobacteriaceae isolates with AZM MICs of ≤16 mg/liter, including those producing a variety of β-lactamases. These data support a potential role for AZM-SPR741 in the treatment of infections due to MDR Enterobacteriaceae .

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 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 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 Impaired Parasite Attachment as Fitness Cost of Metronidazole Resistance in Giardia lamblia

2011 ◽  
Vol 55 (10) ◽  
pp. 4643-4651 ◽  
Author(s):  
Noa Tejman-Yarden ◽  
Maya Millman ◽  
Tineke Lauwaet ◽  
Barbara J. Davids ◽  
Frances D. Gillin ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Cell Lines ◽  
Giardia Lamblia ◽  
Cross Resistance ◽  
Content Type ◽  
Metronidazole Resistance ◽  
High Level ◽  
Plastic Surfaces

ABSTRACTInfections with the diarrheagenic protozoan pathogenGiardia lambliaare most commonly treated with metronidazole (Mz). Treatment failures with Mz occur in 10 to 20% of cases and Mz resistance develops in the laboratory, yet clinically, Mz-resistant (Mzr)G. lambliahas rarely been isolated from patients. To understand why clinical Mzrisolates are rare, we questioned whether Mz resistance entails fitness costs to the parasite. Our studies employed several newly generated and established isogenic Mzrcell lines with stable, high-level resistance to Mz and significant cross-resistance to tinidazole, nitazoxanide, and furazolidone. Oral infection of suckling mice revealed that three of five Mzrcell lines could not establish infection, while two Mzrcell lines infected pups, albeit with reduced efficiencies. Failure to colonize resulted from a diminished capacity of the parasite to attach to the intestinal mucosain vivoand to epithelial cells and plastic surfacesin vitro. The attachment defect was related to impaired glucose metabolism, since the noninfectious Mzrlines consumed less glucose, and glucose promoted ATP-independent parasite attachment in the parental lines. Thus, resistance ofGiardiato Mz is accompanied by a glucose metabolism-related attachment defect that can interfere with colonization of the host. Because glucose-metabolizing pathways are important for activation of the prodrug Mz, it follows that a fitness trade-off exists between diminished Mz activation and reduced infectivity, which may explain the observed paucity of clinical Mzrisolates ofGiardia. However, the data also caution that some forms of Mz resistance do not markedly interfere within vivoinfectivity.

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