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Computational approach towards the design of novel inhibitor against Universal stress protein A to combat multidrug resistant uropathogenic Escherichia coli
Abstract
Uropathogenic Escherichia coli is one of the primary causative agent of urinary tract
infections (UTIs), poses a threat to public health globally. Antibiotics are the only
options for the treatment however emergence of multidrug resistance (MDR)
necessitates search for alternative therapeutics. Administration of antibiotics generated
oxidative stress in this MDR pathogen and enhanced the expression of Universal
stress proteinA (UspA) that helped to overcome the stress and assisted in cell survival.
The aim of the study was to design drug candidates against UspA by in silico
approach. Three-dimensional structure of UspA protein, was homology modelled and
screened against a library of 1,00,000 molecules shortlisted based on Lipinski's rule
and optimum molecular weight selection for good inhibitors from 7.4 million drug like
molecules of ZINC database to discover most potent UspA inhibitors. Three potent
virtual hits were identified based on their different cut of values as binding energy,
hydrogen bonding, ADMET properties. The stability of the protein-ligand complex was
investigated by MD simulation study across 100 ns time scale. The results indicated
that amongst the three potent molecules ZINC000104153710 was found to be the best
fit lead molecule which has showed a high affinity for the catalytic region of UspA, and
formed strong hydrophobic and polar interactions with the amino acid side chains
involved in the binding site. From this study it is concluded that ZINC000104153710
molecule may act as a reliable inhibitor of UspA and may be used to develop a drug
against the MDR uropathogen
... These studies identified small molecule inhibitors of the type II secretion system (T2SS) in A. baumannii [13] and type III secretion system (T3SS) in several Gram-negative pathogens [14]. Similarly, a study from our laboratory identified two lead compounds; ZINC000104153710, and, ZINC000000217308 that efficiently bound to the E. coli UspA [15]. However further in vitro studies must be performed to validate these inhibitor molecules to have antibacterial activity in order to be useful as alternative treatments against MDR E. coli. ...
... In our previous study, a batch of MDR E.coli clinical isolates (n = 25) exhibited high MIC values against three traditional bactericidal antibiotics; CIP, CAZ, GEN [8]. The effect of two lead compounds; ZINC000104153710 and ZINC000000217308 [15] at increasing concentrations (10-100 μg ml −1 ) on the MIC of the bactericidal antibiotics against the MDR E. coli isolates were determined using sub-MIC concentrations of the respective antibiotics. At a concentration of 10 μg ml −1 of each lead compound, the MIC values against the respective antibiotics were reduced to 2-8 fold ( Table 1). ...
... However, the morphological features of the cells in presence of the individual lead compounds after treatment with sub-optimal dosage of the antibiotics; CIP, CAZ, and GEN respectively exhibited a rough surface with non-uniform size. Moreover, the MDR cells revealed a comparable morphology with similar cell size and smooth surface as that of the untreated control in presence of the individual lead compounds respectively (Fig. 4) A previous in silico study showed an effective binding capacity of the lead compounds; ZINC000104153710 and ZINC000000217308 [15] to the E. coli UspA that was overexpressed in the MDR E. coli isolates in presence of sub-MIC dosage of the bactericidal drugs; CIP, CAZ, GEN [8]. Western blot analysis on the MDR E. coli cells treated with the sub-MIC concentration of CIP, CAZ, and GEN respectively in presence of the individual lead compounds with anti-UspA antibody showed a marked reduction in the level of UspA protein compared to the absence of the lead compounds (Fig. 5). ...
The increasing incidence of multidrug resistant uropathogenic E. coli (MDR-UPEC), the most common opportunistic pathogen in urinary tract infections (UTI) pose a global health problem and demands searching for alternative therapeutics. Antibiotics generate oxidative stress in bacteria which results in overexpression of the universal stress protein, UspA that helps in bacterial survival. An in silico study showed that two compounds ZINC000104153710, and ZINC000000217308 effectively bound bacterial UspA. This study aimed to determine the activity of ZINC000104153710, and ZINC000000217308 against bacterial UspA function in MDR-UPEC in vitro. Twenty-five highly MDR-UPEC were screened against ZINC000104153710, and, ZINC000000217308 either alone or in combination with the bactericidal antibiotics; ciprofloxacin (CIP), ceftazidime(CAZ), gentamicin(GEN) respectively by determining minimum inhibitory concentrations (MICs) using a broth microdilution assay. Additionally, the effect of ZINC000104153710, and ZINC000000217308 in the absence and presence of antibiotics on the bacteria was monitored by bacterial growth curve assays, ROS production, structure of the organism by scanning electron microscopy (FESEM) and quantitating UspA using a western blot technique. A 2–8 fold reduction in MIC values against ZINC000104153710, and ZINC000000217308 was observed against all 25 MDR-UPEC isolates in the presence of antibiotics with no alteration in intracellular ROS production. Discrete changes in cell morphology was evident in bacteria treated with ZINC000104153710 or ZINC000000217308 and antibiotics individually by FESEM compared with untreated control. Reduction in the level of UspA protein in bacteria treated with combination of ZINC000104153710 or ZINC000000217308 with individual antibiotics established their ability to inhibit UspA whose expression was elevated in presence of antibiotics alone. Therefore this study validated ZINC000104153710, and ZINC000000217308 as potent inhibitors of bacterial UspA function and indicated their potential as alternative therapeutics to combat the MDR-UPEC.
... USPs are associated not only with bacterial stress tolerance but also with the pathogenicity of pathogenic bacteria, and are important factors for the survival or persistence of various pathogens [78,79]. A. baumannii USPA plays an important role in the pathogenicity of the two most lethal, infectious diseases caused by this bacterial human pathogen, pneumonia and sepsis, and it is an essential component of the virulence mechanism of A. baumannii [31]. ...
... It is clear that the study of USPs has moved from superficial investigations to in-depth examination of the mechanisms involved. In the future, the study of USPs may focus on the following trends: (1) despite their importance, our understanding of the structure of USPs is still insufficiently detailed, particularly that of eukaryotic USPs; (2) although USPs are able to help cells survive under stressful conditions, these proteins follow two completely different mechanisms, namely ATP-dependent USPs play a role in cellular transport, whereas ATP-non-binding USPs may function in the cell cycle [105]; (3) the application of USP research to agriculture may facilitate the development of stress-tolerant crop varieties, and the creation of new green pesticide formulations, using USPs as targets or lead compounds for therapeutic or protective agents; and (4) in the medical field, the study of USPs in drug-resistance mechanisms in pathogenic bacteria is important for the screening of novel therapeutic drugs [79] and the development of related antibodies and vaccines for the prevention and treatment of human diseases. USPs from different plants, which play different roles in vivo (Table 3), are also worthy of research in the future by genetically engineering plants to adapt them to more complex climatic challenges. ...
Universal stress proteins (USPs) exist across a wide range of species and are vital for survival under stressful conditions. Due to the increasingly harsh global environmental conditions, it is increasingly important to study the role of USPs in achieving stress tolerance. This review discusses the role of USPs in organisms from three aspects: (1) organisms generally have multiple USP genes that play specific roles at different developmental periods of the organism, and, due to their ubiquity, USPs can be used as an important indicator to study species evolution; (2) a comparison of the structures of USPs reveals that they generally bind ATP or its analogs at similar sequence positions, which may underlie the regulatory role of USPs; and (3) the functions of USPs in species are diverse, and are generally directly related to the stress tolerance. In microorganisms, USPs are associated with cell membrane formation, whereas in plants they may act as protein chaperones or RNA chaperones to help plants withstand stress at the molecular level and may also interact with other proteins to regulate normal plant activities. This review will provide directions for future research, focusing on USPs to provide clues for the development of stress-tolerant crop varieties and for the generation of novel green pesticide formulations in agriculture, and to better understand the evolution of drug resistance in pathogenic microorganisms in medicine.
... 3D structure of the above nine OsUSP proteins was used as a receptor to find out the binding affinity with three wellestablished inhibitors of E. coli UspA -ZINC000104153710, ZINC000004268284, ZINC000000217308 (Bandyopadhyay et al., 2021). Four kinase inhibitors -fisetin, luteolin, myricetin, quercetin (Cassidy and Setzer, 2010) were used to check their binding affinity toward the kinase domain-containing OsUSPs. ...
... In this present study, we have performed blind docking (Hetényi and van der Spoel, 2002) method for exploration of possible binding sites and binding affinity of our proteins and toward some known USP and kinase inhibitors. In concordance with the previous study on UspA inhibitor in E. coli (Bandyopadhyay et al., 2021), ZINC000104153710 showed the best docking result, thus suggesting having an inhibitory effect on OsUSP activity. Furthermore, studies have found flavonoids acting as an inhibitor toward kinases (Cassidy and Setzer, 2010). ...
... Three-dimensional structures of nine USPs were created using the MODELLER tool of MPI bioinformatics toolkit 14 (Zimmermann et al., 2018;Gabler et al., 2020) 3D structure of the above nine OsUSP proteins was used as a receptor to find out the binding affinity with three wellestablished inhibitors of E. coli UspA -ZINC000104153710, ZINC000004268284, ZINC000000217308 (Bandyopadhyay et al., 2021). Four kinase inhibitors -fisetin, luteolin, myricetin, quercetin (Cassidy and Setzer, 2010) were used to check their binding affinity toward the kinase domain-containing OsUSPs. ...
... In this present study, we have performed blind docking (Hetényi and van der Spoel, 2002) method for exploration of possible binding sites and binding affinity of our proteins and toward some known USP and kinase inhibitors. In concordance with the previous study on UspA inhibitor in E. coli (Bandyopadhyay et al., 2021), ZINC000104153710 showed the best docking result, thus suggesting having an inhibitory effect on OsUSP activity. Furthermore, studies have found flavonoids acting as an inhibitor toward kinases (Cassidy and Setzer, 2010). ...
In a world where climate change is real and its consequences are unprecedented, understanding of the plant adaptive capacity and native stress-responsive machinery is crucial. In recent years, universal stress proteins (USPs) have received much attention in the field of plant science due to their stress-specific transcriptional regulation. This study focuses on the extensive characterization of the USP gene family members in the monocot crop rice (Oryza sativa L. var. japonica). Here, we report a total of 44 USP genes in the rice genome. In silico characterization of these genes showed that domain architecture played a major role in the functional diversification of the USP gene family which holds for all plant USPs. On top of that, a higher conservation of OsUSP members has been exhibited with a monocot genome (Zea mays L.) as compared to a dicot genome (Arabidopsis thaliana L.). Expression profiling of the identified genes led to the discovery of multiple OsUSP genes that showed pronounced transcript alteration under various abiotic stress conditions, indicating their potential role as multi-functional stress-specific modules. Furthermore, expression validation of OsUSP genes using qRT-PCR provided a strong evidence for the utility OsUSP genes in building multi-stress tolerant plants. Altogether, this study provides leads to suitable USP candidates that could be targeted for plant breeding and genetic engineering experiments to develop stress resilient crop species.
... Three-dimensional structures of nine USPs were created using the MODELLER tool of MPI bioinformatics toolkit 14 (Zimmermann et al., 2018;Gabler et al., 2020) 3D structure of the above nine OsUSP proteins was used as a receptor to find out the binding affinity with three wellestablished inhibitors of E. coli UspA -ZINC000104153710, ZINC000004268284, ZINC000000217308 (Bandyopadhyay et al., 2021). Four kinase inhibitors -fisetin, luteolin, myricetin, quercetin (Cassidy and Setzer, 2010) were used to check their binding affinity toward the kinase domain-containing OsUSPs. ...
... In this present study, we have performed blind docking (Hetényi and van der Spoel, 2002) method for exploration of possible binding sites and binding affinity of our proteins and toward some known USP and kinase inhibitors. In concordance with the previous study on UspA inhibitor in E. coli (Bandyopadhyay et al., 2021), ZINC000104153710 showed the best docking result, thus suggesting having an inhibitory effect on OsUSP activity. Furthermore, studies have found flavonoids acting as an inhibitor toward kinases (Cassidy and Setzer, 2010). ...
In a world where climate change is real and its consequences are unprecedented, understanding of the plant adaptive capacity and native stress-responsive machinery is crucial. In recent years, universal stress proteins (USPs) have received much attention in the field of plant science due to their stress-specific transcriptional regulation. This study focuses on the extensive characterization of the USP gene family members in the monocot crop rice (Oryza sativa L. var. japonica). Here, we report a total of 44 USP genes in the rice genome. In silico characterization of these genes showed that domain architecture played a major role in the functional diversification of the USP gene family which holds for all plant USPs. On top of that, a higher conservation of OsUSP members has been exhibited with a monocot genome (Zea mays L.) as compared to a dicot genome (Arabidopsis thaliana L.). Expression profiling of the identified genes led to the discovery of multiple OsUSP genes that showed pronounced transcript alteration under various abiotic stress conditions, indicating their potential role as multi-functional stress-specific modules. Furthermore, expression validation of OsUSP genes using qRT-PCR provided a strong evidence for the utility OsUSP genes in building multi-stress tolerant plants. Altogether, this study provides leads to suitable USP candidates that could be targeted for plant breeding and genetic engineering experiments to develop stress resilient crop species.
... USPs may find applications in the development of stress-responsive sensors and diagnostic tools. Engineered USPs could serve as indicators of environmental stress levels, providing realtime monitoring for industrial processes or environmental conditions [64]. Incorporating these stress proteins into the production of biopharmaceuticals could enhance their resistance to environmental factors, leading to increased shelf life and efficacy. ...
Universal stress proteins (USPs) are widely distributed and play crucial roles in cellular responses to biotic and abiotic stresses. These roles include regulating cell growth and development, cell motility, hypoxia responses, and ion sequestration. With the increasing frequency and intensity of extreme weather events due to climate change, pathogens have developed different strategies to withstand environmental stresses, in which USPs play a significant role in their survival and virulence. In this study, we analyzed the importance of USPs in various organisms, such as archaea, plants, and fungi, as a parameter that influences their survival. We discussed the different types Of USPs and their role, aiming to carry out fundamental research in this field to identify significant constraints for better understanding of USP functions at molecular level. Additionally, we discussed concepts and research techniques that could help overcome these hurdles and facilitate new molecular approaches to better understand and target USPs as important stress adaptation and survival regulators. Although the precise characteristics of USPs are still unclear, numerous innovative uses have already been developed, tested, and implemented. Complementary approaches to basic research and applications, as well as new technology and analytical techniques, may offer insights into the cryptic but crucial activities of USPs in various living systems.
Graphical Abstract
Shows the different environmental stresses faced by plants and microbes and how they respond by generating stress proteins, which are enhanced when stressors trigger organisms and help the organism in stress tolerance and resistance and the pathogenesis of microbes.
Type 2 diabetes mellitus(T2DM) is one of the most common chronic diseases employing abnormal levels of insulin. Enhancing the insulin production is greatly aided by the regulatory mechanisms of the Fractalkine receptor (CX3CR1) system in islet β-cell function. However, elements including a high-fat diet, obesity, and ageing negatively impact the expression of CX3CR1 in islets. CX3CL1/CX3CR1 receptor-ligand complex is now recognized as a novel therapeutic target. It suggests that T2DM-related β-cell dysfunction may result from lower amount of these proteins. We analyzed the differential expression of CX3CR1 gene samples taken from persons with T2DM using data obtained from the GEO database. Homology modeling enabled us to generate the three-dimensional structure of CX3CR1 and a possible binding pocket. The optimized CX3CR1 structure was subjected to rigorous screening against a massive library of 693 million drug-like molecules from the ZINC15 database. This screening process led to the identification of three compounds with strong binding affinity at the identified binding pocket of CX3CR1. To further evaluate the potential of these compounds, molecular dynamics (MD) simulations were conducted over a 50-nanosecond time scale to assess the stability of the protein-ligand complexes. These simulations revealed that ZINC000032506419 emerged as the most promising drug-like compound among the three potent molecules. The discovery of ZINC000032506419 holds exciting promise as a potential therapeutic agent for type 2 diabetes and other related metabolic disorders. These findings pave the way for the development of effective medications to address the complexities of T2DM and its associated metabolic diseases.
Emergence of multidrug resistance (MDR) in uropathogenic E. coli (UPEC) demands alternative therapeutic interventions. Bactericidal antibiotics at their sub-inhibitory concentration stimulate production of reactive oxygen species (ROS) that results in oxidative stress, generates mutations, and alters transcription of different genes. Sub-inhibitory concentration of antibiotics facilitates selection of highly resistant population. Universal stress protein A (uspA) overexpression in MDR-UPEC at sub-inhibitory bactericidal antibiotics concentration was investigated to explore alternative survival strategy against them. Fifty clinical UPEC isolates were screened. Minimum inhibitory concentration (MIC) against three different bactericidal antibiotics (ciprofloxacin, CIP; ceftazidime, CAZ; gentamycin, GEN) was determined by broth dilution method; ROS production by DCFDA and overexpression of uspA by real-time PCR were determined at the sub-inhibitory concentration of antibiotics. DNA ladder formation and SEM studies were performed with drug untreated and treated samples. Statistical analysis was done by Student's t test and Pearson's correlation analysis; 25 out of 50 UPEC exhibited high MIC against CIP (> 200 μg/ml), CAZ (> 500 μg/ml), GEN (> 500 μg/ml), with varied ROS production (p ≤ 0.001) in treated than untreated controls. DNA ladder formation confirmed ROS production in drug-treated samples. SEM analysis revealed unaltered cell morphology in both untreated and drug-treated bacteria. uspA was universally overexpressed in all 25 UPEC. A significant correlation (p ≤ 0.001) between ROS production and uspA overexpression was observed in 19 out of 25 MDR isolates at sub-inhibitory doses of the bactericidal antibiotics. Therefore, this study highlights an alternative strategy that the MDR isolates may acquire when exposed to sub-inhibitory drug concentration for their survival.
The electron conductivity of an extended metal atom chain (EMAC) that consisted of penta-nickel(II) ions bridged by oligo-α-pyridylamino ligands was examined by density functional theory (DFT) and elastic scattering Green’s functions (ESGF) calculations. The calculated results revealed that an intramolecular ferromagnetic (FM) coupling state showed a higher conductivity in comparison with an anti-ferromagnetic (AFM) coupling state. The present results suggest the potential of the complex as a molecular switch as well as a molecular wire.
A priority pollutant Phthalate Esters (PAEs) are widely used as plasticizers and are responsible mainly for carcinogenicity and endocrine disruption in human. For the bioremediation of PAEs, a psychrotolerant Sphingobium yanoikuyae strain P4, capable of utilizing many phthalates di-methyl phthalate (DMP), di-ethyl phthalate (DEP), di-n-butyl phthalate (DBP), di-isobutyl phthalate (DIBP), butyl benzyl phthalate (BBP), and
few Polycyclic Aromatic Hydrocarbons as the sole source of carbon and energy was isolated from Palampur, Kangra, Himachal Pradesh, India. 100% utilization of DBP (1 g L
-1) by the strain was observed within 24 h of incubation at 28°C. Interestingly the strain also degraded DBP completely at 20°C and 15°C within 36 h and 60 h, respectively. Esterase involved in DBP degradation was found to be inducible in nature and intracellular.
Comparative sequence analysis of carboxylesterase enzyme sequences revealed conserved motifs: G-X-S-X-G and -HGG- which were the characteristic peptide motifs reported in different esterases. Structural analysis showed that the enzyme belongs to serine hydrolase superfamily, which has an α/βhydrolase fold. Interaction and binding of DBP to a catalytic Ser184 residue in the esterase enzyme were also analysed. In conclusion, carboxylesterase possess the required active site which may be involved in the catabolism of DBP.
Objective
Complicated urinary tract infections (cUTIs) impose a high burden on healthcare systems and are a frequent cause of hospitalisation. The aims of this paper are to estimate the cost per episode of patients hospitalised due to cUTI and to explore the factors associated with cUTI-related healthcare costs in eight countries with high prevalence of multidrug resistance (MDR).
Design
This is a multinational observational, retrospective study. The mean cost per episode was computed by multiplying the volume of healthcare use for each patient by the unit cost of each item of care and summing across all components. Costs were measured from the hospital perspective. Patient-level regression analyses were used to identify the factors explaining variation in cUTI-related costs.
Setting
The study was conducted in 20 hospitals in eight countries with high prevalence of multidrug resistant Gram-negative bacteria (Bulgaria, Greece, Hungary, Israel, Italy, Romania, Spain and Turkey).
Participants
Data were obtained from 644 episodes of patients hospitalised due to cUTI.
Results
The mean cost per case was €5700, with considerable variation between countries (largest value €7740 in Turkey; lowest value €4028 in Israel), mainly due to differences in length of hospital stay. Factors associated with higher costs per patient were: type of admission, infection source, infection severity, the Charlson comorbidity index and presence of MDR.
Conclusions
The mean cost per hospitalised case of cUTI was substantial and varied significantly between countries. A better knowledge of the reasons for variations in length of stays could facilitate a better standardised quality of care for patients with cUTI and allow a more efficient allocation of healthcare resources. Urgent admissions, infections due to an indwelling urinary catheterisation, resulting in septic shock or severe sepsis, in patients with comorbidities and presenting MDR were related to a higher cost.
Wide diversity of β-lactamases causes resistance to third-generation cephalosporins (3GCs) in Uropathogenic E. coli (UPEC) the frequently encountered nosocomial pathogen creating treatment complications. blaOXA were characterized by genetic diversity and heterogeneity in terms of β-lactam hydrolysis spectrum. In the present study emergence of blaOXA in 3GC resistant nosocomial UPEC was explored. 77(40.5%) E. coli isolates resistant to 3GCs (ceftriazone ceftazidime cefotaxime) were isolated from 190 urine culture positive samples from hospitalized patients clinically diagnosed for urinary tract infection (UTI). Highest resistance was observed against non-β-lactams; ciprofloxacin (100%), levofloxacin (90%), cotrimoxazole (95%) and intermediate resistance against amikacin (55%). 34 (44.15%) and 43 (55.84%) isolates were ESBL producers and β-lactamase inhibitor resistant (BLIR) with varied imepenem (100%, 88.37%) susceptibility respectively. blaOXA (21.58%, 6.97%) was detected either alone or in combination with blaTEM (41.17%, 53.48%), blaCTX-M (5.88%, 0.0%) and blaTEM, blaCTX-M (14.7%, 13.95%) in ESBL and BLIR isolates respectively. blaOXA-type III(95%) carried on IncF type plasmid replicon was predominant with rare incidence of blaOXA-type II(3.33%) and I(1.66%). Phylogenetic background of majority of E. coli isolates belonged to B2 (75.32%) and D (22.07%). ERIC typing analysis indicated that these isolates were very similar and homogeneous. This study for the first time demonstrates high incidence of acquisition of blaOXA-type III in imepenem sensitive 3GC resistant nosocomial UPEC isolates which was independent of their genetic organization. Therefore this study indicates urgent need to implement routine molecular analysis of emerging β-lactamases among UPEC that represent potential sources of clinical failure for commonly prescribed β-lactams.
Leishmania, a protozoan parasite that causes leishmaniasis, affects 1-2 million people every year worldwide. Leishmaniasis is a vector born disease and characterized by a diverse group of clinical syndromes. Current treatment is limited because of drug resistance, high cost, poor safety and low efficacy. The urgent need for potent agents against Leishmania has led to significant advances in the development of novel antileishmanial drugs. β-galactofuranose (β-Galf) is an important component of Leishmanial cell surface matrix and plays a critical role in the pathogenesis of parasite. UDP-galactopyranose mutase (UGM) converts UDP-galactopyranose (UDP-Galp) to UDP-galactofuranose (UDP-Galf) which acts as the precursor for β-Galf synthesis. Due to its absence in human, this enzyme is selected as the potential target in search of new antileishmanial drugs. Three dimensional protein structure model of Leishmania major UGM (LmUGM) has been homology modelled using Trypanosoma cruzi UGM (TcUGM) as a template. The stereochemistry was validated further. We selected already reported active compounds from PubChem database to target the LmUGM. Three compounds (6064500, 44570814 and 6158954) among the top hit occupied the UDP binding site of UGM suggested to work as a possible inhibitor for it. In vitro antileishmanial activity assay was performed with the top ranked inhibitor, 6064500. The 6064500 molecule has inhibited the growth of Leishmania donovani promastigotes significantly. Further, at similar concentrations it has exhibited significantly lesser toxicity than standard drug miltefosine hydrate in mammalian cells.
In recent years, an increase of uropathogenic Escherichia coli (UPEC) strains with Multidrug-resistant (MDR) and Extensively Drug-resistant (XDR) profiles that complicate therapy for urinary tract infections (UTIs) has been observed and has directly impacted costs and extended hospital stays. The aim of this study was to determine MDR- and XDR-UPEC clinical strains, their virulence genes, their phylogenetic groups and to ascertain their relationship with integrons and genetic diversity. From a collection of 500 UPEC strains, 103 were selected with MDR and XDR characteristics. MDR-UPEC strains were mainly associated with phylogenetic groups D (54.87%) and B2 (39.02%) with a high percentage (≥70%) of several fimbrial genes (ecpA, fimH, csgA, and papGII), an iron uptake gene (chuA), and a toxin gene (hlyA). In addition, a moderate frequency (40–70%) of other genes (iutD, tosA, and bcsA) was observed. XDR-UPEC strains were predominantly associated with phylogenetic groups B2 (47.61%) and D (42.85%), which grouped with ≥80 virulence genes, including ecpA, fimH, csgA, papGII, iutD, and chuA. A moderate frequency (40–70%) of the tosA and hlyA genes was observed. The class 1 and 2 integrons that were identified in the MDR- and XDR-UPEC strains were associated with phylogenetic groups D, B2, and A, while the XDR-UPEC strains that were associated with phylogenetic groups B2, D, and A showed an extended-spectrum beta-lactamase (ESBL) phenotype. The modifying enzymes (aadA1, aadB, aacC, ant1, dfrA1, dfrA17, and aadA4) that were identified in the variable region of class 1 and 2 integrons from the MDR strains showed resistance to gentamycin (56.25 and 66.66%, respectively) and trimethoprim-sulfamethoxazole (84.61 and 66.66%, respectively). The MDR- and XDR-UPEC strains were distributed into seven clusters and were closely related to phylogenic groups B2 and D. The diversity analysis by PFGE showed 42.68% of clones of MDR-UPEC and no clonal association in the XDR-UPEC strains. In conclusion, phylogenetic groups including virulence genes are widely associated with two integron classes (1 and 2) in MDR- and XDR-UPEC strains.
In spite of various control measures and eradication methods that have been in progress, schistosomiasis still prevails as one of the most prevalent debilitating parasitic diseases, typically affecting the poor and the underprivileged that are predominantly concentrated in sub-Saharan Africa. The parasitic schistosome blood fluke responsible for causing the disease completes its complex developmental cycle in two hosts: humans and freshwater snails, where they physically undergo gross modifications to endure the different conditions associated with each host. Just like any other organism, the worm possesses mechanisms that help them respond to environmental insults. It has been hypothesized that a special class of proteins known as Universal Stress Proteins (USPs) are up-regulated during sudden environmental changes, thus assisting the worm to tolerate the unfavourable conditions associated with its developmental cycle. The position of praziquantel as the drug of choice against all schistosome infections has been deemed vulnerable due to mounting concerns over drug pressure and so the need for alternative treatment is now a matter of urgency. Therefore, this review seeks to explore the associations and possible roles of USPs in schistosomiasis as well as the functioning of these proteins in the schistosomulae stage in order to develop new therapeutic interventions against this disease.
Universal stress proteins are ubiquitously expressed in bacteria, archaea and plants and other eukaryotes. A general property of USPs is their role in adaptation of bacteria to oxidative stress, high temperature, low pH and/or hypoxia. There is increasing evidence that these proteins facilitate the adaption of bacterial pathogens to the human host environment, thereby facilitating colonisation and pathogenicity. USPs in Mycobacterium tuberculosis are well studied and may play a role in latency of tuberculosis. USP expressed by Acinetobacter baumannii, Listeria monocytogenes and Salmonella enterica serovar Typhimurium are involved in survival in vivo, while USPs expressed in Pseudomonas aeruginosa and Porphyromonas gingivalis are involved in biofilm formation. Burkholderia cepacia complex and Staphylococcus aureus express USPs that play roles in host cell or host protein adhesion. There is also increasing evidence that USPs also bind to antimicrobial agents and may be ideal candidates to target in the future design of new anti-virulence strategies.