Genetic improvement of Egyptian cotton (Gossypium barbadense L.) for high yield and fiber quality properties under semi arid conditions.

Between 2016 and 2018, the Agriculture Research Center's Sakha Agriculture Research Station conducted two rounds of pedigree selection on a segregating population of cotton (Gossypium barbadense L.) using the F2, F3, and F4 generations resulting from crossing Giza 94 and Suvin. In 2016, the top 5% of plants from the F2 population were selected based on specific criteria. The superior families from the F3 generation were then selected to produce the F4 families in 2017, which were grown in the 2018 summer season in single plant progeny rows and bulk experiments with a randomized complete block design of three replications. Over time, most traits showed increased mean values in the population, with the F2 generation having higher Genotypic Coefficient of Variance (GCV) and Phenotypic Coefficient of Variance (PCV) values compared to the succeeding generations for the studied traits. The magnitude of GCV and PCV in the F3 and F4 generations was similar, indicating that genotype had played a greater role than the environment. Moreover, the mean values of heritability in the broad sense increased from generation to generation. Selection criteria I2, I4, and I5 were effective in improving most of the yield and its component traits, while selection criterion I1 was efficient in improving earliness traits. Most of the yield and its component traits showed a positive and significant correlation with each other, highlighting their importance in cotton yield. This suggests that selecting to improveone or more of these traits would improve the others. Families number 9, 13, 19, 20, and 21 were the best genotypes for relevant yield characters, surpassing the better parent, check variety, and giving the best values for most characters. Therefore, the breeder could continue to use these families in further generations as breeding genotypes to develop varieties with high yields and its components.

Lansoprazole interferes with fungal respiration and acts synergistically with amphotericin B against multidrug-resistant Candida auris.

Candida auris has emerged as a problematic fungal pathogen associated with high morbidity and mortality. Amphotericin B (AmB) is the most effective antifungal used to treat invasive fungal candidiasis, with resistance rarely observed among clinical isolates. However, C. auris possesses extraordinary resistant profiles against all available antifungal drugs, including AmB. In our pursuit of potential solutions, we screened a panel of 727 FDA-approved drugs. We identified the proton pump inhibitor lansoprazole (LNP) as a potent enhancer of AmB's activity against C. auris. LNP also potentiates the antifungal activity of AmB against other medically important species of Candida and Cryptococcus. Our investigations into the mechanism of action unveiled that LNP metabolite(s) interact with a crucial target in the mitochondrial respiratory chain (complex III, known as cytochrome bc1). This interaction increases oxidative stress within fungal cells. Our results demonstrated the critical role of an active respiratory function in the antifungal activity of LNP. Most importantly, LNP restored the efficacy of AmB in an immunocompromised mouse model, resulting in a 1.7-log (∼98%) CFU reduction in the burden of C. auris in the kidneys. Our findings strongly advocate for a comprehensive evaluation of LNP as a cytochrome bc1 inhibitor for combating drug-resistant C. auris infections.

Enhanced antifungal activity of posaconazole against Candida auris by HIV protease inhibitors, atazanavir and saquinavir.

The increasing incidence and dissemination of multidrug-resistant Candida auris represents a serious global threat. The emergence of pan-resistant C. auris exhibiting resistance to all three classes of antifungals magnifies the need for novel therapeutic interventions. We identified that two HIV protease inhibitors, atazanavir and saquinavir, in combination with posaconazole exhibited potent activity against C. auris in vitro and in vivo. Both atazanavir and saquinavir exhibited a remarkable synergistic activity with posaconazole against all tested C. auris isolates and other medically important Candida species. In a time-kill assay, both drugs restored the fungistatic activity of posaconazole, resulting in reduction of 5 and 5.6 log10, respectively. Furthermore, in contrast to the individual drugs, the two combinations effectively inhibited the biofilm formation of C. auris by 66.2 and 81.2%, respectively. Finally, the efficacy of the two combinations were tested in a mouse model of C. auris infection. The atazanavir/posaconazole and saquinavir/posaconazole combinations significantly reduced the C. auris burden in mice kidneys by 2.04- (99.1%) and 1.44-log10 (96.4%) colony forming unit, respectively. Altogether, these results suggest that the combination of posaconazole with the HIV protease inhibitors warrants further investigation as a new therapeutic regimen for the treatment of C. auris infections.

Naphthylthiazoles: a class of broad-spectrum antifungals.

Cryptococcal infections remain a major cause of mortality worldwide due to the ability of Cryptococci to pass through the blood-brain barrier (BBB) causing lethal meningitis. The limited number of available therapeutics, which exhibit limited availability, severe toxicity and low tolerability, necessitates the development of new therapeutics. Investigating the antifungal activity of a novel series of naphthylthiazoles provided trans-diaminocyclohexyl derivative 18 with many advantageous attributes as a potential therapeutic for cryptococcal meningitis. Briefly, the antimycotic activity of 18 against cryptococcal strains was highly comparable to that of amphotericin-B and fluconazole with MIC values as low as 1 µg mL-1. Moreover, compound 18 possessed additional advantages over fluconazole; it significantly reduced the intracellular burden of Cryptococci and markedly inhibited cryptococcal biofilm formation. Initial PK assessment of 18 indicated its ability to reach the CNS after oral administration with high permeability, and it maintained therapeutic plasma concentrations for 18 h. Its antifungal activity extended to other clinically relevant strains, such as fluconazole-resistant C. auris.

Morphological and physio-biochemical responses under heat stress in cotton: Overview.

Cotton is an important cash crop in addition to being a fiber commodity, and it plays an essential part in the economies of numerous nations. High temperature is the most critical element affecting its yield from fertilization to harvest. The optimal temperature for root formation is 30 C -35 °C; however, root development ends around 40 °C. Increased temperature, in particular, influences different biochemical and physiological processes associated with cotton plant, resulting in low seed cotton production. Many studies in various agroecological zones used various agronomic strategies and contemporary breeding techniques to reduce heat stress and improve cotton productivity. To attain desired traits, cotton breeders should investigate all potential possibilities, such as generating superior cultivars by traditional breeding, employing molecular techniques and transgenic methods, such as using genome editing techniques. The main objective of this review is to provide the recent information on the environmental factors, such as temperature, heat and drought, influence the growth and development, morphology and physio-chemical alteration associated with cotton. Furthermore, recent advancement in cotton breeding to combat the serious threat of drought and heat stress.

Morphological, pathogenic and genetic diversity in Diplodia seriata associated with black rot canker of apple in India.

Apple cankers are extremely destructive diseases threatening the global apple industry through direct and indirect losses. The population structure of the pathogens is of paramount significance for the development of efficient management strategies. Therefore, phenotypic, pathogenic, and genetic diversity of Diplodia seriata causing black rot canker of apple was investigated in this study. All the isolates were included for investigating the in vitro mycelial growth, conidial dimensions, and pathogenic variability on two-year-old potted apple seedlings. The ISSR approach was used to investigate the molecular diversity of D. seriata. Mycelial growth rates were found to vary significantly amongst the isolates; however, there were no major variations seen between the different geographical groupings of isolates. Pathogenicity tests revealed variations in the size of cankers among the isolates indicating the presence of virulence variability. The isolates were segregated into three virulence groups based on canker length. The Bayesian analyses of ISSR data divided the isolates into two genetic clusters. The genetic clustering of the isolates revealed no relationship with geographical origin of the isolates. Furthermore, no direct relationship of genetic clustering was observed with morphological or pathogenic variability. The ISSR primers revealed very high level of variability in D. seriata; however, no distinct populations of the pathogen existed which is an indication of high level of gene flow between the diverse geographical populations. According to our knowledge, this is the first thorough investigation on the diversity of D. seriata associated with apple black rot canker in India.

Saquinavir potentiates itraconazole's antifungal activity against multidrug-resistant Candida auris in vitro andin vivo.

Candida species are highly opportunistic yeasts that are responsible for serious invasive fungal infections among immunocompromised patients worldwide. Due to the increase in drug resistance and incidence of infections, there is an urgent need to develop new antifungals and to identify co-drugs that can sensitize drug-resistant Candida to antifungals. The objective of this study was to assess the effect of saquinavir on the activity of azole antifungals against C. auris. The in vitro interaction of saquinavir and three azole antifungals (itraconazole, voriconazole, and fluconazole) was evaluated against a panel of C. auris isolates. The itraconazole/saquinavir combination exhibited a synergistic (SYN) relationship against all C. auris isolates tested with the fractional inhibitory concentration index ranging from 0.03 to 0.27. Moreover, a time-kill kinetics assay revealed that saquinavir restored the itraconazole's fungistatic activity against C. auris. Furthermore, saquinavir restored itraconazole's antifungal activity against other clinically important Candida species. The mechanistic investigation indicated that saquinavir significantly inhibited efflux pumps, glucose utilization, and ATP synthesis in Candida. Finally, a murine model of C. auris infection was used to evaluate the efficacy of the itraconazole/saquinavir combination in the presence of ritonavir (as a pharmacokinetic enhancer). The combination significantly reduced the fungal burden in the kidneys by 0.93-log10 colony-forming units (88%) compared to itraconazole alone. This study identified that saquinavir exhibits a potent SYN relationship in combination with itraconazole against Candida species, which warrants further consideration.

Candida auris is a multi-drug resistant fungal pathogen with limited treatment options. In this study, we identified that the antiviral drug, saquinavir, is capable of synergizing and restoring the activity of antifungals against C. auris.

Lopinavir and ritonavir act synergistically with azoles against Candida auris in vitro and in a mouse model of disseminated candidiasis.

INTRODUCTION AND OBJECTIVES: The emergence of Candida auris has created a global health challenge. Azole antifungals are the most affected antifungal class because of the extraordinary capability of C. auris to develop resistance against these drugs. Here, we used a combinatorial therapeutic approach to sensitize C. auris to azole antifungals. METHODS AND RESULTS: We have demonstrated the capability of the HIV protease inhibitors lopinavir and ritonavir, at clinically relevant concentrations, to be used with azole antifungals to treat C. auris infections both in vitro and in vivo. Both lopinavir and ritonavir exhibited potent synergistic interactions with the azole antifungals, particularly with itraconazole against 24/24 (100%) and 31/34 (91%) of tested C. auris isolates, respectively. Furthermore, ritonavir significantly interfered with the fungal efflux pump, resulting in a significant increase in Nile red fluorescence by 44%. In a mouse model of C. auris systemic infection, ritonavir boosted the activity of lopinavir to work synergistically with fluconazole and itraconazole and significantly reduced the kidney fungal burden by a 1.2 log (∼94%) and 1.6 log (∼97%) CFU, respectively. CONCLUSION: Our results urge further comprehensive assessment of azoles and HIV protease inhibitors as a novel drug regimen for the treatment of serious invasive C. auris infections.

Biocontrol agent of root-knot nematode Meloidogyne javanica and root-rot fungi, Fusarium solani in okra morphological, anatomical characteristics and productivity under greenhouse conditions.

This study was conducted to evaluate the ability of some fungal culture filtrate, as biocontrol agents against okra wilt caused by Fusarium solani. and Meloidogyne javanica. In the present study, fungal culture filtrates (FCFs) of Aspergillus terreus (1), Aspergillus terreus (2), Penicillium chrysogenum, and Trichoderma spp. were tested against M. javanica in vitro. The effects of P. chrysogenum and Trichoderma spp. (FCFs) in controlling root-rot fungi and root-knot nematode disease complex on okra plants were studied under greenhouse conditions (In vivo). In vitro experiment, the results revealed cumulative rate of J2s mortality of M. javanica reached to 97.67 and 95% by P. chrysogenum and Trichoderma spp., respectively, after 72 h. incubation. Additionally, Trichoderma spp exhibited the most effective inhibitory activity against the pathogen's radial growth, with a percentage of 68%. P. chrysogenum ranked second with 53.88%, while A. terreus (2) demonstrated the weakest inhibitory effect of 24.11%. T6 [Nematode infection (M. javanica) + Fungus infection (F. solani) + Overflowed with fungal culture filtrate (P. chrysogenum)] and T8 [Nematode infection (M. javanica) + Fungus infection (F. solani) + spray with fungal culture filtrate (P. chrysogenum)] had the greatest effects on nematode galling indices on okra roots and substantially reduced the reproductive factors in the greenhouse (In vivo experiment). T6 was the best treatment to decrease disease severity, as reached (28%) relatively. On the other hand, T12 [(Fungus infection (F. solani) + (Dovex 50% fungicide with irrigation water)] recorded the lowest disease severity reaching (8%) relatively. The results showed that nematode infection or fungus infection or both decreased all studied anatomical characteristics of okra root, stem, and leaves. We concluded from this study that root-knot nematode and root-rot fungi were reduced by using fungal culture filtrates and could improve plant growth.

Fingerprint Stimulated Raman Scattering Imaging Unveils Ergosteryl Ester as a Metabolic Signature of Azole-Resistant Candida albicans.

Candida albicans (C. albicans), a major fungal pathogen, causes life-threatening infections in immunocompromised individuals. Fluconazole (FLC) is recommended as first-line therapy for treatment of invasive fungal infections. However, the widespread use of FLC has resulted in increased antifungal resistance among different strains of Candida, especially C. albicans, which is a leading source of hospital-acquired infections. Here, by hyperspectral stimulated Raman scattering imaging of single fungal cells in the fingerprint window and pixel-wise spectral unmixing, we report aberrant ergosteryl ester accumulation in azole-resistant C. albicans compared to azole-susceptible species. This accumulation was a consequence of de novo lipogenesis. Lipid profiling by mass spectroscopy identified ergosterol oleate to be the major species stored in azole-resistant C. albicans. Blocking ergosterol esterification by oleate and suppressing sterol synthesis by FLC synergistically suppressed the viability of C. albicans in vitro and limited the growth of biofilm on mouse skin in vivo. Our findings highlight a metabolic marker and a new therapeutic strategy for targeting azole-resistant C. albicans by interrupting the esterified ergosterol biosynthetic pathway.

Atazanavir Resensitizes Candida auris to Azoles.

Candida auris represents an urgent health threat. Here, we identified atazanavir as a potent drug capable of resensitizing C. auris clinical isolates to the activity of azole antifungals. Atazanavir was able to significantly inhibit the efflux pumps, glucose transport, and ATP synthesis of all tested isolates of C. auris. In addition, the combination of itraconazole with atazanavir-ritonavir significantly reduced the burden of azole-resistant C. auris in murine kidneys by 1.3 log10 (95%), compared to itraconazole alone.

Comparative physiological and biochemical mechanisms in diploid, triploid, and tetraploid watermelon (Citrullus lanatus L.) grafted by branches.

Seed production for polyploid watermelons is costly, complex, and labor-intensive. Tetraploid and triploid plants produce fewer seeds/fruit, and triploid embryos have a harder seed coat and are generally weaker than diploid seeds. In this study, we propagated tetraploid and triploid watermelons by grafting cuttings onto gourd rootstock (C. maxima × C. mochata). We used three different scions: the apical meristem (AM), one-node (1N), and two-node (2N) branches of diploid, triploid, and tetraploid watermelon plants. We then evaluated the effects of grafting on plant survival, some biochemical traits, oxidants, antioxidants, and hormone levels at different time points. We found significant differences between the polyploid watermelons when the 1N was used as a scion. Tetraploid watermelons had the highest survival rates and the highest levels of hormones, carbohydrates, and antioxidant activity compared to diploid watermelons, which may explain the high compatibility of tetraploid watermelons and the deterioration of the graft zone in diploid watermelons. Our results show that hormone production and enzyme activity with high carbohydrate content, particularly in the 2-3 days after transplantation, contribute to a high survival rate. Sugar application resulted in increased carbohydrate accumulation in the grafted combination. This study also presents an alternative and cost-effective approach to producing more tetraploid and triploid watermelon plants for breeding and seed production by using branches as sprouts.

Genetic analysis of yield traits in Egyptian cotton crosses (Gossypium barbdense L.) under normal conditions.

To generate high-yielding cultivars with favorable fiber quality traits, cotton breeders can use information about combining ability and gene activity within a population to locate elite parents and potential F1 crosses. To this end, in the current study, twelve cotton parents (eight genotypes as female parents and four testers) and their F1 crosses obtained utilizing the linex tester mating design were evaluated for their general and specialized combining abilities (GCA and SCA, respectively) of yield traits. The findings showed that for all the investigated variables, variances owing to genotypes, parents, crosses, and parent vs cross showed extremely significant (P ≤ 0.01) differences. Additionally, throughout the course of two growing seasons, the mean squares for genotypes (parents and crosses) showed strong significance for all the variables under study. The greatest and most desired means for all the examined qualities were in the parent G.94, Pima S6, and tester G.86. The best crossings for the qualities examined were G.86 (G.89 × G.86), G.93 × Suvin, and G.86 × Suvin. The parents' Suvin, G89x G86 and TNB were shown to have the most desired general combining ability effects for seed cotton yield/plant, lint yield/plant, boll weight, number of bolls/plants, and lint index, while Suvin, G.96 and pima S6 were preferred for favored lint percentage. For seed cotton yield, lint percentage, boll weight, and number of bolls per plant per year, the cross-G.86 x (G.89 × G.86) displayed highly significant specific combining ability impacts. The crosses G.86 × Suvin, Kar x TNB, G.93 × Suvin, and G.93 × TNB for all the studied traits for each year and their combined were found to have highly significant positive heterotic effects relative to better parent, and they could be used in future cotton breeding programs for improving the studied traits.

Cytokinin Production by Azospirillum brasilense Contributes to Increase in Growth, Yield, Antioxidant, and Physiological Systems of Wheat (Triticum aestivum L.).

Plant growth-promoting rhizobacteria are known to associate with several cereal crops. The rhizobacterium exerts its function by synthesizing diverse arrays of phytohormones, such as cytokinin (Ck). However, it is difficult to determine the plant growth promotion when a bacterium produces many different kinds of phytohormones. Therefore, to assess the involvement of Ck in growth promotion and activation of antioxidant and physiological systems, we set up this experiment. Wheat seeds (Triticum aestivum L.) were inoculated with Azospirillum brasilense RA-17 (which produces zeatin type Ck) and RA-18 (which failed to produce Ck). Results showed that seed inoculation with RA-17 significantly improved growth and yield-related parameters compared with RA-18. The activity of enzymes, proline contents, and endogenous hormonal levels in wheat kernels were improved considerably with RA-17 than with RA-18. Strain RA-17 enhanced grain assimilation more than strain RA-18 resulting in a higher crop yield. These results suggest that microbial Ck production may be necessary for stimulating plant growth promotion and activating antioxidant and physiological systems in wheat.

In ovo Inoculation of Bacillus subtilis and Raffinose Affects Growth Performance, Cecal Microbiota, Volatile Fatty Acid, Ileal Morphology and Gene Expression, and Sustainability of Broiler Chickens (Gallus gallus).

Banning antibiotic growth promoters has negatively impacted poultry production and sustainability, which led to exploring efficient alternatives such as probiotics, probiotics, and synbiotics. Effect of in ovo injection of Bacillus subtilis, raffinose, and their synbiotics on growth performance, cecal microbial population and volatile fatty acid concentration, ileal histomorphology, and ileal gene expression was investigated in broilers (Gallus gallus) raised for 21 days. On 300 h of incubation, a total of 1,500 embryonated eggs were equally allotted into 10 groups. The first was non-injected (NC) and the remaining in ovo injected with sterile distilled water (PC), B. subtilis 4 × 105 and 4 × 106 CFU (BS1 and BS2), Raffinose 2 and 3 mg (R1 and R2), B. subtilis 4 × 105 CFU + raffinose 2 mg (BS1R1), B. subtilis 4 × 105 CFU + raffinose 3 mg (BS1R2), B. subtilis 4 × 106 CFU + raffinose 2 mg (BS2R1), and B. subtilis 4 × 106 CFU + raffinose 3 mg (BS2R2). At hatch, 60 chicks from each group were randomly chosen, divided into groups of 6 replicates (10 birds/replicate), and fed with a corn-soybean-based diet. In ovo inoculation of B. subtilis and raffinose alone or combinations significantly improved body weight, feed intake, and feed conversion ratio of 21-day-old broilers compared to NC. Cecal concentrations of butyric, pentanoic, propionic, and isobutyric acids were significantly elevated in R1, R2, BS2R1, and BS2R2, whereas isovaleric and acetic acids were significantly increased in R1 and BS2R1 compared to NC. Cecal microbial population was significantly altered in treated groups. Ileal villus height was increased (p < 0.001) in BS1, R2, and BS2R2 compared to NC. The mRNA expression of mucin-2 was upregulated (p < 0.05) in synbiotic groups except for BS1R1. Vascular endothelial growth factor (VEGF) expression was increased (p < 0.05) in BS2, R1, BS1R1, and BS1R2 compared to NC. SGLT-1 expression was upregulated (p < 0.05) in all treated birds except those of R1 group compared to NC. The mRNA expressions of interleukin (IL)-2 and toll-like receptor (TLR)-4 were downregulated (p < 0.05) in BS2 and R1 for IL-2 and BS1R1 and BS2R2 for TLR-4. It was concluded that in ovo B. subtilis, raffinose, and synbiotics positively affected growth performance, cecal microbiota, gut health, immune responses, and thus the sustainability of production in 21-day-old broilers.

Identification of four compounds from the Pharmakon library with antifungal activity against Candida auris and species of Cryptococcus.

There is an urgent need to develop novel antifungals. In this study, we screened 1600 compounds for antifungal activity against Cryptococcus neoformans and Candida auris. We evaluated 4 promising compounds against 24 additional isolates of Cr. neoformans, Ca. auris, Cr. deuterogattii, and Cr. gattii. The four compounds, dequalinium chloride (DQC), bleomycin sulfate (BMS), pentamidine isethionate salt (PIS), and clioquinol (CLQ), varied in their efficacy against these pathogens but were generally more effective against cryptococci. The compounds exerted their antifungal effect via multiple mechanisms, including interference with the capsule of cryptococci and induction of hyphal-like morphology in Ca. auris. Our results indicate that DQC, BMS, PIS, and CLQ represent potential prototypes for the future development of antifungals. LAY SUMMARY: Fungal infections can be lethal and the options to fight them are scarce. We tested 1600 molecules for their ability to control the growth of two important fungal pathogens, namely Candida auris and species of Cryptococcus. Four of these compounds showed promising antifungal activities.

Transcriptome Profiling to Dissect the Role of Genome Duplication on Graft Compatibility Mechanisms in Watermelon.

Watermelon (Citrullus lanatus) is a popular crop worldwide. Compared to diploid seeded watermelon, triploid seedless watermelon cultivars are in great demand. Grafting in triploid and tetraploid watermelon produces few seedlings. To learn more about how genome duplication affects graft compatibility, we compared the transcriptomes of tetraploid and diploid watermelons grafted on squash rootstock using a splicing technique. WGCNA was used to compare the expression of differentially expressed genes (DEGs) between diploid and tetraploid watermelon grafted seedlings at 0, 3, and 15 days after grafting (DAG). Only four gene networks/modules correlated significantly with phenotypic characteristics. We found 11 genes implicated in hormone, AOX, and starch metabolism in these modules based on intramodular significance and RT-qPCR. Among these genes, two were linked with IAA (r2 = 0.81), one with ZR (r2 = 0.85) and one with POD (r2 = 0.74). In the MElightsteelblue1 module, Cla97C11G224830 gene was linked with CAT (r2 = 0.81). Two genes from the MEivory module, Cla97C07G139710 and Cla97C04G077300, were highly linked with SOD (r2 = 0.72). Cla97C01G023850 and Cla97C01G006680 from the MEdarkolivegreen module were associated with sugars and starch (r2 = 0.87). Tetraploid grafted seedlings had higher survival rates and hormone, AOX, sugar, and starch levels than diploids. We believe that compatibility is a complicated issue that requires further molecular research. We found that genome duplication dramatically altered gene expression in the grafted plants' IAA and ZR signal transduction pathways and AOX biosynthesis pathways, regulating hormone levels and improving plant survival.

Field screening of diverse wheat germplasm for determining their adaptability to semi-arid climatic conditions.

Wheat (Triticum aestivum L.) is an important staple food crop for one third of global population and important crop for securing future food security. Rapid changes in the climate on global scale could be a threat for future food security. This situation urges plant breeders to explore the genetic potential of existing wheat germplasm. This study screened forty diverse wheat genotypes for their yield under two different agroclimatic conditions, i.e., Layyah and Dera Ghazi Khan, Pakistan. Data relating to plant height, peduncle length, flag leaf area, spike length, number of spikelets, number of grains per spike, thousand grain weight, chlorophyll content and grain yield were recorded. The tested wheat genotypes significantly differed for grain yield and related traits. Grain yield was positively correlated with plant height, spike length, spike number, flag leaf length, number of grains per spike, and 1000-grain weight. Biplot obtained from the cluster analysis by Euclidean method grouped the studied genotypes in 3 different groups. The genotypes exhibited 10.77% variability within quadrants, whereas 72.36% variability was recorded between quadrants according to clustering. Dendrogram grouped the tested genotypes into two main clusters. The main cluster "I" comprised of 2 genotypes, i.e., 'Seher-2006' and 'AS-2002'. The cluster "II" contained 38 genotypes based on Euclidian values. Genotypes within same cluster had smaller D2 values compared to those belonging to other clusters. The genetic relationships of genotypes provide useful information for breeding programs. Overall, the results revealed that genotypes 'Line 9733', 'Bhakar-2002', 'Line A9' and 'SYN-46' had better yield and yield stability under climatic conditions of southern Punjab. Therefore, these genotypes could be recommended for general cultivation in the study region.

Evaluation of bisphenylthiazoles as a promising class for combating multidrug-resistant fungal infections.

To minimize the intrinsic toxicity of the antibacterial agent hydrazinyloxadiazole 1, the hydrazine moiety was replaced with ethylenediamine (compound 7). This replacement generated a potent antifungal agent with no antibacterial activity. Notably, use of a 1,2-diaminocyclohexane moiety, as a conformationally-restricted isostere for ethylenediamine, potentiated the antifungal activity in both the cis and trans forms of N-(5-(2-([1,1'-biphenyl]-4-yl)-4-methylthiazol-5-yl)-1,3,4-oxadiazol-2-yl)cyclohexane-1,2-diamine (compounds 16 and 17). Both compounds 16 and 17 were void of any antibacterial activity; nonetheless, they showed equipotent antifungal activity in vitro to that of the most potent approved antifungal agent, amphotericin B. The promising antifungal effects of compounds 16 and 17 were maintained when assessed against an additional panel of 26 yeast and mold clinical isolates, including the Candida auris and C. krusei. Furthermore, compound 17 showed superior activity to amphotericin B in vitro against Candida glabrata and Cryptococcus gattii. Additionally, neither compound inhibited the normal human microbiota, and both possessed excellent safety profiles and were 16 times more tolerable than amphotericin B.

Potent Synergistic Interactions between Lopinavir and Azole Antifungal Drugs against Emerging Multidrug-Resistant Candida auris.

The limited therapeutic options and the recent emergence of multidrug-resistant Candida species present a significant challenge to human medicine and underscore the need for novel therapeutic approaches. Drug repurposing appears as a promising tool to augment the activity of current azole antifungals, especially against multidrug-resistant Candida auris In this study, we evaluated the fluconazole chemosensitization activities of 1,547 FDA-approved drugs and clinical molecules against azole-resistant C. auris This led to the discovery that lopinavir, an HIV protease inhibitor, is a potent agent capable of sensitizing C. auris to the effect of azole antifungals. At a therapeutically achievable concentration, lopinavir exhibited potent synergistic interactions with azole drugs, particularly with itraconazole against C. auris (fractional inhibitory concentration index [ΣFICI] ranged from 0.04 to 0.09). Additionally, the lopinavir/itraconazole combination enhanced the survival rate of C. auris-infected Caenorhabditis elegans by 90% and reduced the fungal burden in infected nematodes by 88.5% (P < 0.05) relative to that of the untreated control. Furthermore, lopinavir enhanced the antifungal activity of itraconazole against other medically important Candida species, including C. albicans, C. tropicalis, C. krusei, and C. parapsilosis Comparative transcriptomic profiling and mechanistic studies revealed that lopinavir was able to significantly interfere with the glucose permeation and ATP synthesis. This compromised the efflux ability of C. auris and consequently enhanced the susceptibility to azole drugs, as demonstrated by Nile red efflux assays. Altogether, these findings present lopinavir as a novel, potent, and broad-spectrum azole-chemosensitizing agent that warrants further investigation against recalcitrant Candida infections.