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Background We previously reported that the tomato glycoalkaloid tomatine inhibited the growth of Trichomonas vaginalis strain G3, Tritrichomonas foetus strain D1, and Tritrichomonas foetus-like strain C1 that cause disease in humans and farm and domesticated animals. The increasing prevalence of antibiotic resistance requires development of new tools to enhance or replace medicinal antibiotics. Methods Wild tomato plants were harvested and divided into leaves, stems, and fruit of different colors: green, yellow, and red. Samples were freeze dried and ground with a handheld mill. The resulting powders were evaluated for their potential anti-microbial effects on protozoan parasites, bacteria, and fungi. A concentration of 0.02% (w/v) was used for the inhibition of protozoan parasites. A high concentration of 10% (w/v) solution was tested for bacteria and fungi as an initial screen to evaluate potential anti-microbial activity and results using this high concentration limits its clinical relevance. Results Natural powders derived from various parts of tomato plants were all effective in inhibiting the growth of the three trichomonads to varying degrees. Test samples from leaves, stems, and immature ‘green’ tomato peels and fruit, all containing tomatine, were more effective as an inhibitor of the D1 strain than those prepared from yellow and red tomato peels which lack tomatine. Chlorogenic acid and quercetin glycosides were present in all parts of the plant and fruit, while caffeic acid was only found in the fruit peels. Any correlation between plant components and inhibition of the G3 and C1 strains was not apparent, although all the powders were variably effective. Tomato leaf was the most effective powder in all strains, and was also the highest in tomatine. S. enterica showed a minor susceptibility while B. cereus and C. albicans fungi both showed a significant growth inhibition with some of the test powders. The powders inhibited growth of the pathogens without affecting beneficial lactobacilli found in the normal flora of the vagina. Conclusions The results suggest that powders prepared from tomato leaves, stems, and green tomato peels and to a lesser extent from peels from yellow and red tomatoes offer potential multiple health benefits against infections caused by pathogenic protozoa, bacteria, and fungi, without affecting beneficial lactobacilli that also reside in the normal flora of the vagina.

Human trichomoniasis, caused by the pathogenic parasitic protozoan Trichomonas vaginalis, is the most common non-viral sexually transmitted disease that contributes to reproductive morbidity in affected women and possibly to prostate cancer in men. Tritrichomonas foetus strains cause the disease trichomoniasis in farm animals (cattle, bulls, pigs) and diarrhea in domestic animals (cats and dogs). Because some T. vaginalis strains have become resistant to the widely used drug metronidazole, there is a need to develop alternative treatments, based on safe natural products that have the potential to replace and/or enhance the activity of lower doses of metronidazole. To help meet this need, this overview collates and interprets worldwide reported studies on the efficacy of structurally different classes of food, marine, and medicinal plant extracts and some of their bioactive pure compounds against T. vaginalis and T. foetus in vitro and in infected mice and women. Active food extracts include potato peels and their glycoalkaloids α-chaconine and α-solanine, caffeic and chlorogenic acids, and quercetin; the tomato glycoalkaloid α-tomatine; theaflavin-rich black tea extracts and bioactive theaflavins; plant essential oils and their compounds (+)-α-bisabolol and eugenol; the grape skin compound resveratrol; the kidney bean lectin, marine extracts from algae, seaweeds, and fungi and compounds that are derived from fungi; medicinal extracts and about 30 isolated pure compounds. Also covered are the inactivation of drug-resistant T. vaginalis and T. foetus strains by sensitized light; anti-trichomonad effects in mice and women; beneficial effects of probiotics in women; and mechanisms that govern cell death. The summarized findings will hopefully stimulate additional research, including molecular-mechanism-guided inactivations and human clinical studies, that will help ameliorate adverse effects of pathogenic protozoa.

Writing is an active learning strategy strongly linked to student engagement. Student-authored learning narratives can reveal powerful self-beliefs that can either activate or inhibit success. In this targeted study of the aspect of student engagement most associated with self-beliefs (i.e., self-efficacy), students in separate sections of an introductory college biology course taught by the same professor were divided into experimental and control groups. The experimental group participated in an additional 1-unit required study skills component featuring writing-to-learn and self-efficacy development strategies. One hundred forty “pre” and “post” student self-efficacy narratives written in both cohorts were scored and also thematically coded. Scoring revealed a Cohen’s effect size d = 0.63 for the experimental group, but only d = 0.28 for control. Thus, writing appears to activate student self-efficacy most if it is part of a deliberate and sustained campaign. Gains seemed particularly impactful for struggling students, as the experimental group also saw significantly fewer students, with unmet fundamental skills, earning Ds and Fs in the course than those in the control group. Subsequent student interviews were also analyzed and informed recommendations for future research and pedagogical practice.

Herein we report the synthesis of 21 novel small molecules inspired by metronidazole and Schiff base compounds. The compounds were evaluated against Trichomonas vaginalis and cross-screened against other pathogenic protozoans of clinical relevance. Most of these compounds were potent against T. vaginalis, exhibiting IC

Copper-promoted azide-alkyne cycloadditions were attempted to synthesize a series of variedly functionalized 1H-1,2,3-triazole-linked isatin-ferrocene, ferrocenylmethoxy-isatin and isatin-ferrocenyl-chalcone conjugates. The synthesized scaffolds were assayed for their inhibitory activity against T. vaginalis as well as several common normal human flora bacteria. The observed inhibitory activities against T. vaginalis and undetectable inhibition of microflora bacteria suggest that these compounds may be specific against trichomonad protozoa and could serve as a new scaffold for synthesis of novel compounds against this important human pathogen.

Clinical cases of metronidazole resistant Trichomonas vaginalis infections have spurred interest in drug discovery against this protozoal parasite. We have carried out structure-activity studies using mononuclear palladium(II) complexes containing salicylaldiminato thiosemicarbazones on a patient isolate of Trichomonas vaginalis highly resistant to the FDA-approved drug metronidazole. A small library of sixteen compounds were analysed on this resistant isolate. Interestingly, compared with our previous analysis of a metronidazole sensitive strain, susceptibility of this resistant isolate to four of the six most potent compounds was observed. Two compounds had similar IC50 values between the resistant strain and a previously analysed sensitive line. Palladium(II) salicylaldiminato thiosemicarbazone complexes may represent, with further development, a new drug discovery direction for treating clinical cases of metronidazole-resistant T. vaginalis. The most potent compound had an IC50 value of 15 μM on parasite growth and showed no effects on common normal flora bacteria and no morphological effects when tested on cultured mammalian cells.

Trichomonas vaginalis causes the most common, nonviral sexually transmitted infection. Only metronidazole (Mz) and tinidazole are approved for treating trichomoniasis, yet resistance is a clinical problem. The gold(I) complex, auranofin, is active against T. vaginalis and other protozoa but has significant human toxicity. In a systematic structure-activity exploration, we show here that diversification of gold(I) complexes, particularly as halides with simple C1-C3 trialkyl phosphines or as bistrialkyl phosphine complexes, can markedly improve potency against T. vaginalis and selectivity over human cells compared to that of the existing antirheumatic gold(I) drugs. All gold(I) complexes inhibited the two most abundant isoforms of the presumed target enzyme, thioredoxin reductase, but a subset of compounds were markedly more active against live T. vaginalis than the enzyme, suggesting that alternative targets exist. Furthermore, all tested gold(I) complexes acted independently of Mz and were able to overcome Mz resistance, making them candidates for the treatment of Mz-refractory trichomoniasis.

Trichomoniasis in humans, caused by the protozoal parasite Trichomonas vaginalis, is the most common non-viral sexually transmitted disease, while Tritrichomonas foetus causes trichomonosis, an infection of the gastrointestinal tract and diarrhea in farm animals and domesticated cats. As part of an effort to determine the inhibitory effects of plant-based extracts and pure compounds, seven commercially available cherry tomato varieties were hand-peeled, freeze-dried, and pounded into powders. The anti-trichomonad inhibitory activities of these peel powders at 0.02% concentration determined using an in vitro cell assay varied widely from 0.0% to 66.7% against T. vaginalis G3 (human), from 0.9% to 66.8% for T. foetus C1 (feline), and from 0.0% to 81.3% for T. foetus D1 (bovine). The organic Solanum lycopersicum var. cerasiforme (D) peels were the most active against all three trichomonads, inhibiting 52.2% (G3), 66.8% (C1), and 81.3% (D1). Additional assays showed that none of the powders inhibited the growth of foodborne pathogenic bacteria, pathogenic fungi, or non-pathogenic lactobacilli. Tomato peel and pomace powders with high content of described biologically active compounds could serve as functional food and feed additives that might help overcome adverse effects of wide-ranging diseases and complement the treatment of parasites with the anti-trichomonad drug metronidazole.

Reaction of dihydroartemisinin (DHA) with 4-methyl-4′-carboxy-2,2′-bipyridine yielded the new ester derivative L1. Six novel organometallic half-sandwich chlorido Rh(III) and Ir(III) complexes (1–6) containing pentamethylcyclopentadienyl, (Cp*), tetramethylphenylcyclopentadienyl (Cpxph), or tetramethylbiphenylcyclopentadienyl (Cpxbiph), and N,N-chelated bipyridyl group of L1, have been synthesized and characterized. The complexes were screened for inhibitory activity against the Plasmodium falciparum 3D7 (sensitive), Dd2 (multi-drug resistant) and NF54 late stage gametocytes (LSGNF54), the parasite strain Trichomonas vaginalis G3, as well as A2780 (human ovarian carcinoma), A549 (human alveolar adenocarcinoma), HCT116 (human colorectal carcinoma), MCF7 (human breast cancer) and PC3 (human prostate cancer) cancer cell lines. They show nanomolar antiplasmodial activity, outperforming chloroquine and artemisinin. Their activities were also comparable to dihydroartemisinin. As anticancer agents, several of the complexes showed high inhibitory effects, with Ir(III) complex 3, containing the tetramethylbiphenylcyclopentadienyl ligand, having similar IC50 values (concentration for 50% of maximum inhibition of cell growth) as the clinical drug cisplatin (1.06–9.23 μM versus 0.24–7.2 μM, respectively). Overall, the iridium complexes (1–3) are more potent compared to the rhodium derivatives (4–6), and complex 3 emerges as the most promising candidate for future studies.

Control of fungal pathogens is increasingly problematic due to the limited number of effective drugs available for antifungal therapy. Conventional antifungal drugs could also trigger human cytotoxicity associated with the kidneys and liver, including the generation of reactive oxygen species. Moreover, increased incidences of fungal resistance to the classes of azoles, such as fluconazole, itraconazole, voriconazole, or posaconazole, or echinocandins, including caspofungin, anidulafungin, or micafungin, have been documented. Of note, certain azole fungicides such as propiconazole or tebuconazole that are applied to agricultural fields have the same mechanism of antifungal action as clinical azole drugs. Such long-term application of azole fungicides to crop fields provides environmental selection pressure for the emergence of pan-azole-resistant fungal strains such as Aspergillus fumigatus having TR34/L98H mutations, specifically, a 34 bp insertion into the cytochrome P450 51A (CYP51A) gene promoter region and a leucine-to-histidine substitution at codon 98 of CYP51A. Altogether, the emerging resistance of pathogens to currently available antifungal drugs and insufficiency in the discovery of new therapeutics engender the urgent need for the development of new antifungals and/or alternative therapies for effective control of fungal pathogens. We discuss the current needs for the discovery of new clinical antifungal drugs and the recent drug repurposing endeavors as alternative methods for fungal pathogen control.

Plant-derived anthraquinones were evaluated in cell assays for their inhibitory activities against the parasitic protozoa Trichomonas vaginalis human strain G3 that causes the sexually transmitted disease trichomoniasis in women, Tritrichomonas foetus bovine strain D1 that causes sexually transmitted diseases in farm animals (bulls, cows, and pigs), Tritrichomonas foetus-like strain C1 that causes diarrhea in domestic animals (cats and dogs), and bacteria and fungi. The anthraquinones assessed for their inhibitory activity were anthraquinone, aloe-emodin (1,8-dihydroxy-3-hydroxymethylanthraquinone), anthrarufin (1, 5-dihydroxyanthraquinone), chrysazin (1,8-dihydroxyanthraquinone), emodin (1,3,8-trihydroxy-6-methylanthraquinone), purpurin (1,2,4-trihydroxyanthraquinone), and rhein (1,8-dihydroxy-3-carboxyanthraquinone). Their activities were determined in terms of IC50 values, defined as the concentration that inhibits 50% of the cells under the test conditions and calculated from linear dose response plots for the parasitic protozoa, and zone of inhibition for bacteria and fungi, respectively. The results show that the different substituents on the anthraquinone ring seem to influence the relative potency. Analysis of the structure–activity relationships in protozoa indicates that the aloe-emodin and chrysazin with the highest biological activities merit further study for their potential to help treat the diseases in women and domestic and farm animals. Emodin also exhibited antifungal activity against Candida albicans. The suggested mechanism of action and the additional reported beneficial biological properties of anthraquinones suggest that they have the potential to ameliorate a broad spectrum of human diseases.

Potato peel, a waste product of the potato processing industry, is high in bioactive compounds. We investigated the in vitro antitrichomonad activity of potato peel powders prepared from commercial Russet, red, purple, and fingerling varieties as well as several known potato components, alkaloids and phenolic compounds, against three pathogenic strains of trichomonads. Trichomonas vaginalis is a sexually transmitted protozoan parasite that causes the human disease trichomoniasis. Two distinct strains of the related Tritrichomonas fetus infect cattle and cats. The glycoalkaloids α-chaconine and α-solanine were highly active against all parasite lines, while their common aglycone solanidine was only mildly inhibitory. α-Solanine was several times more active than α-chaconine. The phenolic compounds caffeic and chlorogenic acids and quercetin were mildly active against the parasites. Most of the potato peel samples were at least somewhat active against all three trichomonad species, but their activities were wide-ranging and did not correspond to their glycoalkaloid and phenolic content determined by HPLC. The two Russet samples were the most active against all three parasites. The purple potato peel sample was highly active against bovine and mostly inactive against feline trichomonads. None of the test substances were inhibitory toward several normal microflora species, suggesting the potential use of the peels for targeted therapeutic treatments against trichomonads.

Fourteen novel arene RuII , and cyclopentadienyl (Cpx ) RhIII and IrIII complexes containing an N,N'-chelated pyridylimino- or quinolylimino ligand functionalized with the antimalarial drug sulfadoxine have been synthesized and characterized, including three by X-ray crystallography. The rhodium and iridium complexes exhibited potent antiplasmodial activity with IC50 values of 0.10-2.0 μm in either all, or one of the three Plasmodium falciparum assays (3D7 chloroquine sensitive, Dd2 chloroquine resistant and NF54 sexual late stage gametocytes) but were only moderately active towards Trichomonas vaginalis. They were active in both the asexual blood stage and the sexual late stage gametocyte assays, whereas the clinical parent drug, sulfadoxine, was inactive. Five complexes were moderately active against Mycobacterium tuberculosis (IC50

In this study, we outline the synthesis of isatin–ferrocenyl chalcone and 1H-1,2,3-triazole-tethered isatin–ferrocene conjugates along with their antimicrobial evaluation against the human mucosal pathogen Trichomonas vaginalis. The introduction of a triazole ring among the synthesized conjugates improved the activity profiles with most of the compounds in the library, exhibiting 100% growth inhibition in a preliminary susceptibility screen at 100 μM. IC50 determination of the most potent compounds in the set revealed an inhibitory range between 2 and 13 μM. Normal flora microbiome are unaffected by these compounds, suggesting that these may be new chemical scaffolds for the discovery of new drugs against trichomonad infections.

The apicomplexan parasite Sarcocystis neurona is the primary etiologic agent of equine protozoal myeloencephalitis (EPM), a serious neurologic disease of horses. Many horses in the U.S. are at risk of developing EPM; approximately 50% of all horses in the U.S. have been exposed to S. neurona and treatments for EPM are 60–70% effective. Advancement of treatment requires new technology to identify new drugs for EPM. To address this critical need, we developed, validated, and implemented a high-throughput screen to test 725 FDA-approved compounds from the NIH clinical collections library for anti-S. neurona activity. Our screen identified 18 compounds with confirmed inhibitory activity against S. neurona growth, including compounds active in the nM concentration range. Many identified inhibitory compounds have well-defined mechanisms of action, making them useful tools to study parasite biology in addition to being potential therapeutic agents. In comparing the activity of inhibitory compounds identified by our screen to that of other screens against other apicomplexan parasites, we found that most compounds (15/18; 83%) have activity against one or more related apicomplexans. Interestingly, nearly half (44%; 8/18) of the inhibitory compounds have reported activity against dopamine receptors. We also found that dantrolene, a compound already formulated for horses with a peak plasma concentration of 37.8 ± 12.8 ng/ml after 500 mg dose, inhibits S. neurona parasites at low concentrations (0.065 μM [0.036–0.12; 95% CI] or 21.9 ng/ml [12.1–40.3; 95% CI]). These studies demonstrate the use of a new tool for discovering new chemotherapeutic agents for EPM and potentially providing new reagents to elucidate biologic pathways required for successful S. neurona infection., Graphical abstract Image 1, Highlights • A novel high-throughput screen for Sarcocystis neurona growth is developed. • Eighteen novel inhibitory compounds are identified from a drug repurposing library. • Dantrolene, a currently available equine drug, also inhibits parasite growth. • Identified inhibitory compounds share activity against related parasites.

The fungal antioxidant system is one of the targets of the redox-active polyene antifungal drugs, including amphotericin B (AMB), nystatin (NYS), and natamycin (NAT). Besides medical applications, NAT has been used in industry for preserving foods and crops. In this study, we investigated two parameters (pH and food ingredients) affecting NAT efficacy. In the human pathogen, Aspergillus fumigatus, NAT (2 to 16 μg mL−1) exerted higher activity at pH 5.6 than at pH 3.5 on a defined medium. In contrast, NAT exhibited higher activity at pH 3.5 than at pH 5.6 against foodborne fungal contaminants, Aspergillus flavus, Aspergillus parasiticus, and Penicillium expansum, with P. expansum being the most sensitive. In commercial food matrices (10 organic fruit juices), food ingredients differentially affected NAT antifungal efficacy. Noteworthily, NAT overcame tolerance of the A. fumigatus signaling mutants to the fungicide fludioxonil and exerted antifungal synergism with the secondary metabolite, kojic acid (KA). Altogether, NAT exhibited better antifungal activity at acidic pH against foodborne fungi, however, the ingredients from commercial food matrices presented greater impact on NAT efficacy compared to pH values. Comprehensive determination of parameters affecting NAT efficacy and improved food formulation will promote sustainable food/crop production, food safety, and public health.

Trichomonas vaginalis, the most common nonviral sexually transmitted parasite, causes ∼283 million trichomoniasis infections annually and is associated with pregnancy complications and increased risk of HIV-1 acquisition. The antimicrobial drug metronidazole is used for treatment, but in a fraction of clinical cases, the parasites can become resistant to this drug. We undertook sequencing of multiple clinical isolates and lab derived lines to identify genetic markers and mechanisms of metronidazole resistance. Reduced representation genome sequencing of ∼100 T. vaginalis clinical isolates identified 3,923 SNP markers and presence of a bipartite population structure. Linkage disequilibrium was found to decay rapidly, suggesting genome-wide recombination and the feasibility of genetic association studies in the parasite. We identified 72 SNPs associated with metronidazole resistance, and a comparison of SNPs within several lab-derived resistant lines revealed an overlap with the clinically resistant isolates. We identified SNPs in genes for which no function has yet been assigned, as well as in functionally-characterized genes relevant to drug resistance (e.g., pyruvate:ferredoxin oxidoreductase). Transcription profiles of resistant strains showed common changes in genes involved in drug activation (e.g., flavin reductase), accumulation (e.g., multidrug resistance pump), and detoxification (e.g., nitroreductase). Finally, we identified convergent genetic changes in lab-derived resistant lines of Tritrichomonas foetus, a distantly related species that causes venereal disease in cattle. Shared genetic changes within and between T. vaginalis and Tr. foetus parasites suggest conservation of the pathways through which adaptation has occurred. These findings extend our knowledge of drug resistance in the parasite, providing a panel of markers that can be used as a diagnostic tool.

Microbial eukaryotes (protists) are important components of terrestrial and aquatic environments, as well as animal and human microbiomes. Their relationships with metazoa range from mutualistic to parasitic and zoonotic (i.e., transmissible between humans and animals). Despite their ecological importance, our knowledge of protists in urban environments lags behind that of bacteria, largely due to a lack of experimentally validated high-throughput protocols that produce accurate estimates of protist diversity while minimizing non-protist DNA representation. We optimized protocols for detecting zoonotic protists in raw sewage samples, with a focus on trichomonad taxa. First, we investigated the utility of two commonly used variable regions of the 18S rRNA marker gene, V4 and V9, by amplifying and Sanger sequencing 23 different eukaryotic species, including 16 protist species such as Cryptosporidium parvum, Giardia intestinalis, Toxoplasma gondii, and species of trichomonad. Next, we optimized wet-lab methods for sample processing and Illumina sequencing of both regions from raw sewage collected from a private apartment building in New York City. Our results show that both regions are effective at identifying several zoonotic protists that may be present in sewage. A combination of small extractions (1 mL volumes) performed on the same day as sample collection, and the incorporation of a vertebrate blocking primer, is ideal to detect protist taxa of interest and combat the effects of metazoan DNA. We expect that the robust, standardized methods presented in our workflow will be applicable to investigations of protists in other environmental samples, and will help facilitate large-scale investigations of protistan diversity. Electronic supplementary material The online version of this article (doi:10.1007/s00248-017-0996-9) contains supplementary material, which is available to authorized users.

A series of N-alkyl tethered C-5 functionalized bis-isatins were synthesized and evaluated for antimicrobial activity against pathogenic microorganisms. The preliminary evaluation studies revealed the compound 4t, with an optimal combination of bromo-substituent at the C-5 position of isatin ring along with propyl chain linker being most active among the synthesized series exhibiting an IC50 value of 3.72 μM against Trichomonas vaginalis while 4j exhibited an IC50 value of 14.8 μM against Naegleria fowleri, more effective than the standard drug Miltefosine. The compound 3f with an octyl spacer length was the most potent among the series against Giardia lamblia with an IC50 of 18.4 μM while 3d exhibited an IC50 of 23 μM against Entamoeba histolytica. This library was also screened against the fungal pathogen Aspergillus parasiticus. A number of the compounds demonstrated potency against this fungus, illustrating a possible broad-spectrum activity. Furthermore, an evaluation of these synthesized compounds against a panel of normal flora bacteria revealed them to be non-cytotoxic, demonstrating the selectivity of these compounds. This observation, in combination with previous studies that isatin is non-toxic to humans, presents a new possible scaffold for drug discovery against these important protozoal pathogens of humans and animals.

Isonicotinyl and pyrazinyl ferrocenyl-derived complexes were prepared using various hydrazides and ferrocenyl aldehydes. Three heterobimetallic complexes were also synthesized from the Schiff base-derived isonicotinyl ferrocene complex using various platinum group metal dimers based on ruthenium, rhodium and iridium. All complexes were evaluated in vitro for antimycobacterial and antiparasitic activity. Against Mycobacterium tuberculosis H37Rv, the platinum group metal complexes showed glycerol-dependent antimycobacterial activity. The antiplasmodial activities against the NF54 chloroquine-sensitive strain of Plasmodium falciparum of some compounds were moderate, while some complexes also showed promising activity against Trichomonas vaginalis. Incorporation of the ferrocenyl-salicylaldimine moiety resulted in enhanced antimicrobial activity compared to the non-ferrocenyl compound in some cases. The bimetallic iridium-ferrocene isonicotinyl complex exhibited superior antitrichomonal activity relative to its organic counterpart, isoniazid. Furthermore, all these compounds, when screened on several normal flora bacteria of humans, showed no effect on the microbiome, emphasizing the selection of these compounds for these pathogens. The promising antimicrobial activities of the complexes thus supports incorporation of ferrocene as part of existing antimicrobial therapies in order to alter their biological activities favorably.

Current antifungal interventions have often limited efficiency in treating fungal pathogens, particularly those resistant to commercial drugs or fungicides. Antifungal drug repurposing is an alternative intervention strategy, whereby new utility of various marketed, non-antifungal drugs could be repositioned as novel antifungal agents. In this study, we investigated “chemosensitization„ as a method to improve the efficiency of antifungal drug repurposing, wherein combined application of a second compound (viz., chemosensitizer) with a conventional, non-antifungal drug could greatly enhance the antifungal activity of the co-applied drug. Redox-active natural compounds or structural derivatives, such as thymol (2-isopropyl-5-methylphenol), 4-isopropyl-3-methylphenol, or 3,5-dimethoxybenzaldehyde, could serve as potent chemosensitizers to enhance antifungal activity of the repurposed drug bithionol. Of note, inclusion of fungal mutants, such as antioxidant mutants, could also facilitate drug repurposing efficiency, which is reflected in the enhancement of antifungal efficacy of bithionol. Bithionol overcame antifungal (viz., fludioxonil) tolerance of the antioxidant mutants of the human/animal pathogen Aspergillus fumigatus. Altogether, our strategy can lead to the development of a high efficiency drug repurposing design, which enhances the susceptibility of pathogens to drugs, reduces time and costs for new antifungal development, and abates drug or fungicide resistance.

When a global pandemic hits during a longitudinal study of biology student success, researchers can unearth rich information about student resilience. By sharing case studies from two demographically different midsized 4-year institutions, this article illustrates the aspects of student self-efficacy beliefs that were undercut by the shift to emergency remote instruction (ERI) in introductory biology courses in Spring 2020: agency and belonging. By assessing student predictions of exam performance and analyzing themes from 276 student narrative surveys, we highlight the power of a careful balance between cognitive and social interventions to help students recover. Students in this study showed a 50% loss of efficacy beliefs after ERI (midsemester) but were able to improve to at least 75% above starting efficacy beliefs after instructor interventions. Thus, we also show how academic efficacy is highly malleable and is mediated in relationships. In turn, we demonstrate a new assessment model that uses student narrative writing to reveal "invisible" threats to students' perceptions of their capacity to succeed. Finally, we generalize from their findings to provide recommendations for effective strategies for supporting those students for whom every semester feels like a pandemic.

Trichomoniasis, caused by the protozoan parasite Trichomonas vaginalis , is the most common, non-viral, sexually transmitted infection in the world, but only two closely related nitro drugs are approved for its treatment. New antimicrobials against trichomoniasis remain an urgent need. Several organic gold compounds were tested for activity against T. vaginalis thioredoxin reductase (TrxR) in cell-free systems as well as for activity against different trichomonads in vitro and in a murine infection model. The organic gold(I) compounds auranofin and chloro(diethylphenylphosphine)gold(I) inhibited TrxR in a concentration-dependent manner in assays with recombinant purified reductase and in cytoplasmic extracts of T. vaginalis transfected with a haemagglutinin epitope-tagged form of the reductase. Auranofin potently suppressed the growth of three independent clinical T. vaginalis isolates as well as several strains of another trichomonad ( Tritrichomonas foetus ) in a 24 h-assay, with 50% inhibitory concentrations of 0.7–2.5 µM and minimum lethal concentrations of 2–6 µM. The drug also compromised the ability of the parasite to overcome oxidant stress, supporting the notion that auranofin acts, in part, by inactivating TrxR-dependent antioxidant defences. Chloro(diethylphenylphosphine)gold(I) was 10-fold less effective against T. vaginalis in vitro than auranofin. Oral administration of auranofin for 4 days cleared the parasites in a murine model of vaginal T. foetus infection without displaying any apparent adverse effects. The approved human drug auranofin may be a promising agent as an alternative treatment of trichomoniasis in cases when standard nitro drug therapies have failed.

Bioisosteric ferrocenyl-containing quinolines and ferrocenylamines containing organosilanes and their carbon analogues, were prepared and fully characterised. The molecular structures of two ferrocenyl-containing quinolines, determined using single-crystal X-ray diffraction, revealed that the compounds crystallise in a folded conformation. The compounds were screened for their antiplasmodial activity against the chloroquine-sensitive (NF54) and CQ-resistant (Dd2) strains of P. falciparum, as well as for their cytotoxicity against Chinese Hamster Ovarian (CHO) cells. The ferrocenyl-containing quinolines displayed activities in the low nanomolar range (6–36 nM), and showed selectivity towards parasites. β-Haematin inhibition assays suggest that the compounds may in part act via the inhibition of haemozoin formation, while microsomal metabolic stability studies reveal that the ferrocenyl-containing quinolines are rapidly metabolised in liver microsomes. Further, antitrichomonal screening against the metronidazole-sensitive (G3) strain of the mucosal pathogen T. vaginalis revealed that the quinoline-based compounds displayed superior parasite growth inhibition when compared to the ferrocenylamines. The library was also tested E. coli and on Lactobacilli spp. found as part of the normal flora of the human microbiome and no effect on growth in vitro was observed, supporting the observation that these compounds are specific for eukaryotic pathogens.

A series of mono- and multimeric polyamine-containing ferrocenyl complexes containing a quinoline motif were prepared. The complexes were characterised by standard techniques. The molecular structure of the monomeric salicylaldimine derivative was elucidated using single crystal X-ray diffraction and was consistent with the proposed structure. The antiplasmodial activity of the compounds were evaluated in vitro against both the NF54 (chloroquine-sensitive) and K1 (chloroquine-resistant) strains of Plasmodium falciparum. The polyamine derivatives exhibit good resistance index values suggesting that these systems are beneficial in overcoming the resistance experienced by chloroquine. Mechanistic studies suggest that haemozoin formation may be the target of these quinoline complexes in the parasite. Some of the complexes exhibit moderate to high cytotoxicity against WHCO1 oesophageal cancer cells in vitro. The monomeric ferrocenyl-amine complexes exhibit potent activity against this particular cell line. The complexes were also screened against the G3 strain of Trichomonas vaginalis and the salicylaldimine complexes demonstrated promising activity at the tested concentration. All of these compounds show no inhibitory effect on several common normal flora bacteria, indicative of their selectivity for eukaryotic pathogens and cancer.

There has been a persistent effort to improve efficacy of conventional antimycotic drugs. However, current antimycotic interventions have often limited efficiency in treating fungal pathogens, especially those resistant to drugs. Considering development of entirely new antimycotic drugs is a capital-intensive and time-consuming process, we investigated an alternative approach termed drug repurposing whereby new utility of various marketed, non-antifungal drugs could be repositioned as novel antimycotic agents. As a proof of concept, we applied chemosensitization as a new screening strategy, where combined application of a second compound, viz., chemosensitizer, with a conventional drug could enhance antifungal efficacy of the drug co-applied. Unlike the conventional combination therapy, a chemosensitizer itself does not necessarily have to possess an antifungal activity, but the chemosensitizer significantly debilitates defense systems of pathogens to drugs, enabling improved identification of antifungal activity of off-patent drugs. Of note, inclusion of fungal mutants, such as antioxidant mutants, could facilitate drug repurposing process by enhancing the sensitivity of antifungal screening. Altogether, our strategy could lead to high efficiency drug repurposing, which enhances the drug susceptibility of targeted fungal pathogens.

Parasitic infections like amebiasis, trichomoniasis, and giardiasis are major health threats with their widespread harmful consequences in tropical and subtropical regions of the world. FDA approved various types of nitro-imidazoles such as ornidazole, benznidazole and secnidazole are widely used medications against anaerobic infections but have lower efficacies than metronidazole (MTZ). MTZ is the current drug of choice for amebiasis, giardiasis and trichomoniasis but it has several adverse effects and potential resistance is a concern. In order to develop alternative antimicrobials, a library of 1H-1,2,3-triazole-tethered metronidazole-isatin conjugates has been synthesized using Huisgen’s azide-alkyne cycloaddition reaction and evaluated for their amebicidal, anti-trichomonal and anti-giardial potential. Most of the synthesized conjugates exhibited comparable activities with that of the standard drug MTZ against Trichomonas vaginalis and Tritrichomonas foetus while better activities were observed against Entamoeba histolytica and Giardia lamblia. Conjugates 9d and 10a were found to be 2-3 folds more potent than MTZ against E. histolytica and 8-16 folds more potent than MTZ against G. lamblia. Further analysis of these compounds on fungi and bacteria did not show inhibitory activity, demonstrating their specific anti-protozoal properties.

Growing resistance to antimicrobial drugs is an urgent life‐threatening problem, forcing medicinal chemists to redesign current drug scaffolds. Derivatization of known drugs to circumvent microbial resistance mechanisms is now an established strategy. The international UK, South African, Australian and USA collaboration of P. Chellan, P. J. Sadler et al. reported in the Full Paper on page 10078 ff., shows that organometallic conjugation of the antibacterial drug sulfadoxine has a remarkable effect on activity. Sulfadoxine has little activity towards various microbial strains, including Plasmodium falciparum and Mycobacterium tuberculosis, but introduction of half‐sandwich rhodium and iridium fragments dramatically “switched on” activity, so providing new drug leads to fight resistance.

Ferrocenyl azines containing salicylaldimine motifs were prepared by Schiff-base condensation of salicylaldehyde hydrazones and (dimethylamino)methyl ferrocenecarboxaldehyde. Their corresponding Rh(I) complexes were prepared by reaction of the various ferrocenyl azines with [RhCl(COD)] 2 (where COD = 1,5-cyclooctadiene) to yield heterobimetallic complexes. The compounds were characterized using standard spectroscopic and analytical techniques. The characterization data suggests that the ferrocenyl azine acts as a bidentate donor. The rhodium(I) centre binds to the imine nitrogen and phenolic oxygen of the salicylaldimine, forming a neutral complex. The compounds were screened against the NF54 chloroquine-sensitive (CQS) and K1 chloroquine-resistant (CQR) strains of Plasmodium falciparum . The ferrocene-containing salicylaldimines exhibited weak to moderate activity across both parasite strains. The heterometallic complexes exhibited enhanced activity compared to the ferrocenyl azines in both strains. Most of the compounds exhibited enhanced activity in the resistant strain compared to the sensitive strain. Inhibition of haemozoin formation was considered as a possible mechanism of action of these compounds and indeed they exhibited β-haematin inhibition activity, albeit weaker than chloroquine. All compounds were also screened against the G3 strain of Trichomonas vaginalis . The compounds inhibited no more than 50% parasite growth at the tested concentration. One complex exhibited moderate cytotoxicity against WHCO1 oesophageal cancer cells.

The resistance of Plasmodium falciparum, the causative agent of malaria, against quinine and chloroquine along with the lack of malaria vaccines has encouraged the development of various synthetic strategies towards biologically active scaffolds. An emerging strategy in medicinal chemistry, termed molecular hybridization, involves the covalent fusion of two or more drugs, active compounds, and/or pharmacophoric units into a hybrid compound, with fascinating activities and multiple but not essentially simultaneous pharmacological targets. 4-Aminoquinolines are considered as promising antimalarials and 4-aminoquinoline hybridization is considered as an attractive and feasible approach for the development of new molecular frameworks for averting and delaying the emergence of drug resistance along with improved efficacy. The present review article describes the recent developments on the 4-aminoquinoline-hybridization towards the development of new antimalarials.

Background Plants produce secondary metabolites that often possess widespread bioactivity, and are then known as phytochemicals. We previously determined that several phytochemical-rich food-derived preparations were active against pathogenic foodborne bacteria. Trichomonads produce disease (trichomoniasis) in humans and in certain animals. Trichomonads are increasingly becoming resistant to conventional modes of treatment. It is of interest to test bioactive, natural compounds for efficacy against these pathogens. Methods Using a cell assay, black tea, green tea, grape, pomegranate, and jujube extracts, as well as whole dried jujube were tested against three trichomonads: Trichomonas vaginalis strain G3 (found in humans), Tritrichomonas foetus strain D1 (found in cattle), and Tritrichomonas foetus-like organism strain C1 (found in cats). The most effective of the test substances was subsequently tested against two metronidazole-resistant Trichomonas vaginalis strains, and on normal mucosal flora. Results Black tea extract inhibited all the tested trichomonads, but was most effective against the T. vaginalis organisms. Inhibition by black tea was correlated with the total and individual theaflavin content of the two tea extracts determined by HPLC. Metronidazole-resistant Trichomonas vaginalis strains were also inhibited by the black tea extract. The response of the organisms to the remaining preparations was variable and unique. We observed no effect of the black tea extract on common normal flora bacteria. Conclusions The results suggest that the black tea, and to a lesser degree green tea, grape seed, and pomegranate extracts might present possible natural alternative therapeutic agents to treat Trichomonas vaginalis infections in humans and the related trichomonad infections in animals, without negatively affecting the normal flora.