International Journal of Current Research and Review
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IJCRR - 4(7), April, 2012

Pages: 128-140

Date of Publication: 18-Apr-2012


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ROLE OF CHAPERONES IN BACTERIAL PATHOGENICITY - A NEW THERAPEUTIC STRATEGY

Author: Balagurunathan R, Shanthi J

Category: General Sciences

Abstract:There is an upsurge in the resistance pattern of bacterial pathogens demanding new therapeutic targets to keep in pace with the infectious organisms. This review discusses harnessing the virulence factors of microorganisms as drug targets that are produced to cope with demanding and rapidly changing environments during establishment in the host. It would be promising to develop small molecule inhibitors targeting specifically the stress proteins, so-called molecular chaperones that assist the protein folding machinery. There are several natural products that bind specifically to components of the chaperone machinery of microbial pathogens have been identified. Many successful pathogens have developed robust haperone systems to conquer the stressful environments in the host environmental challenges, such as oxidative bursts that are often triggered in response to infection. Heat shock proteins are also linked for the emergence of drug resistance and hence targeting sites unique to the bacterial pathogens can be exploited for therapy, chaperons are already viewed as targets for many human ailments like protein aggregation diseases and cancer. This review discusses new insights in exploiting bacterial chaperones as drug targets and their role in pathogenicity.

Keywords: Hsp/HSP, heat shock protein; HspR, heat shock protein receptor; Csr1, cellular stress response protein; Cpx, extra cytoplasmic stress.

Full Text:

INTRODUCTION
Molecular chaperones from bacteria to humans are a highly conserved class of proteins and represent a significant proportion of the total protein content of all living cells. Many heat Shock Proteins function as molecular chaperones and perform important functions in protein folding, unfolding or translocation, assembly and disassembly of protein complexes, in reversing polypeptide unfolding, preventing protein aggregation, and repairing proteins that have been damaged or misfolded by stress (Craig, 1996). Under normal conditions, molecular chaperones are present at low concentrations in cells, but under stress conditions they accumulate to high levels (Kohler et al., 2002) and therefore enable cells to survive. Thus, chaperones are important in both normal and stressed cells. During infection, the molecular chaperones production increases in both pathogen and host cells [Steinhoff et al., 1994). When entering the host from the environment, a pathogen is confronted with several changes, some of which under stress due to temperature, pH and pO2 and changes the natural host resistance mechanisms, phagocytes receptor). Manipulation of either of these factors alters heat shock response and also influences bacterial virulence (Gophna and Ron, 2003). In the case of Helicobacter pylorus, survival in human gastric mucosa requires it to withstand constantly fluctuating environments and low pH conditions. H. pylori responds to environmental changes by modulating a regulator of heat shock protein genes called Csr1 (cellular stress response protein1; hspR is one of the genes modulated by Csr1). Consistent with the possibility that pathogens regulate stress responses to effective virulence, and H. pylori mutant for the csr1 gene showed attenuated infection in a mouse model indicating that genes involved in stress tolerance are critical for H. pylori virulence (Barnard et al., 2004). However, in Mycobacterium tuberculosis, inactivation of hspR and the overexpression of Dna K cause an enhanced clearance of the bacterium in the mouse model of tuberculosis (Gupta et al., 2008). It appears that increased synthesis of DnaK primes the immune system early during infection possibly resulting in increased bacterial clearance. This example indicates that mere overexpression of heat shock proteins may not always confer virulence to bacteria as in the case with induction of heat shock proteins by fluoroquinolones in E.coli correlated well with DNA relaxation but not with cell death (Tohru Mizushima, 1997). Thus the timing and possibly the magnitude of expression needs to be regulated for their cytoprotective effects. One of the best known examples of the role of heat shock proteins in bacterial pathogenesis is Listeria monocytogenes infection in host macrophages. After being phagocytosed into the host, Listeria can be digested upon fusion of the phagosome with an endosomal compartment. However, the bacteria rely on a member of Hsp100 family called ClpC to overcome this consequence. Expression of ClpC in the phagosome allows Listeria to be released from the phagosome into the host cytoplasm where it undergoes multiplication (Nair et al., 2000). Experiments with a clpC deletion strain of Listeria showed accumulation of the bacteria in phagosomes resulting in a significant reduction of bacterial load in a mouse model of infection. While the precise mechanism by which ClpC mediates bacterial exit from the phagosome is not known, it is possible that its interaction with phagosome membrane proteins may be involved. In Brucella suis, Campylobacter jejuni and Salmonella enterica serovar Typhimurium, deletion of DnaK results in compromised growth in macrophages or inability to colonize mice (Konkel et al., 1998). The role for another member of Hsp100 family, ClpB, was shown in Francisella tularensis infection of macrophages. ClpB was essential for F. tularensis to replicate in target organs and cause pathogenesis in mice (Melbom et al., 2008). These studies clearly indicate that intracellular pathogens rely upon their endogenous chaperone machinery to survive and establish an infection within their hosts. Besides these examples there are several reports that suggest a role for bacterial chaperones at the cell surface, as adhesions for invading the host cell or in signaling the immune system. Both the Hsp60 and Hsp70 classes of chaperones have been implicated in this role. In addition, there are also examples where bacteria have found ways to recruit or target host chaperones to enhance bacterial growth and overcome host defense (Henderson et al., 2006). It is apparent that bacteria have mainly exploited their heat shock protein functions to cope with host defense mechanisms triggered in response to infections; additional roles in invasion and multiplication have also been suggested in some of the cases.

Antibiotic stress for the induction of chaperones
Resistance to antibiotics typically occurs as a result of drug inactivation or modification, target alteration or reduced accumulation associated with decreased permeability and/ or increased efflux. The majority of these mechanisms of resistance depend on the rapid over expression of different kinds of protein (Peleg et al., 2008). Challenge of S. aureus with cell wall-active antibiotic initiates an extensive program of gene and protein expression. A large number of genes, including ones encoding proteins involved in cell wall metabolism and stress responses were up regulated by oxacillin, Dcycloserine or bacitracin. This response may represent the transcriptional signature of a cell wall-stress stimulon induced in response to cell wall-active agents. An insertional inactivation in the middle of DnaK, a member of the cell wall stress stimulon, using a kanamycin resistance gene, in S. aureus strains RN450, SH1000, and COL resulted in mutants that grew poorly at temperature above 45°C (Utaida, 2003). DnaK increased more than fourfold after 60 min of exposure to a subinhibitory concentration of antibiotic, and GroEL levels doubled. Furthermore, Acinetobacter baumannii cells pretreated for 30 min at 45°C had an increased ability to survive antibiotic exposure compared with cells pretreated at physiological temperatures. These results suggest that the chaperones DnaK and GroEL could play an important role in the stress response caused by streptomycin in A.baumannii. (Karen Cardoso, 2010). In S. aureus, the Hsp100/Clp ATPases have been extensively studied and they have been shown to play important roles in stress tolerance, intracellular replication in eukaryotic epithelial cells, biofilm formation, expression of extracellular toxins, and pathogenicity in a murine model of infection (Chatterjee et al., 2005). The lack of a functional DnaK reduces oxacillin and methicillin tolerance in S. aureus. The mutation in DnaK had increased the susceptibility of methicillin-resistant strain COL to the cell-wall-active antibiotics oxacillin and methicillin. In the case of the methicillinsusceptible strain SH1000, deletion of DnaK did not reduce the oxacillin MIC, but it had led to a significantly reduced survival after oxacillin treatment. The decreased oxacillin MIC of the DnaK mutant of strain COL, and the decreased persistence of the DnaK mutant of strain SH1000, suggested that protein damage does occur as a result of challenge with cell-wall active antibiotics, and that DnaK plays a role in dealing with these damaged proteins. In Staphylococcus aureus, a mutation in the DnaK gene increased the susceptibility of the methicillin-resistant strain COL to the antibiotics oxacillin and methicillin (Singh et al., 2007). In S. aureus, HSPs are thought to be involved in responses to antibiotics because they are induced when the cell wall is subjected to antibiotic stress (Utaida et al., 2003). HSPs are up regulated at the transcriptional and translational levels by different kinds of antibiotic and that this up regulation could improve the ability of the cell to cope with stress caused by antimicrobials and perhaps acts simultaneously with the antibiotic resistance machinery to maintain cell survival. Some studies have suggested that the role for HSPs in the bacterial stress response due to antibiotics. Yamaguchi et al., 2003 demonstrated that the chaperones DnaK and GroEL have an effect on the antimicrobial activity of the fluoroquinolone, levofloxacin in E. coli and briefed that chaperones might contribute to quinolone resistance because they sequester the aggregates that accumulate in cells exposed to fluoroquinolones. Furthermore, mutations in the DnaK, GroEL and Lon genes increased bacterial susceptibility to levofloxacin. Recent studies have demonstrated that sub inhibitory concentrations of the antimicrobials gentamicin and tobramycin induced a set of genes that affect the interaction of Pseudomonas aeruginosa with host cells, including the gene encoding Lon protease, which is known to play a role in protein quality control (Marr et al., 2007). Sparfloxacin induces DnaK and GroEL proteins, the major heat shock proteins of E. coli, in a dose-dependent manner. A large number of genes, including ones encoding proteins involved in cell wall metabolism and stress responses were up regulated by oxacillin, D-cycloserine or bacitracin. Penicillin dose-dependently increased clpL levels but decreased pbp2x levels, because ClpL is induced by heat shock and other stresses (Kwon et al., 2003), pneumococcal survival seems to depend on competition between the amounts of ClpL and PBP2x. Low-level stress may induce ClpL and increase cell resistance to penicillin compared to normal cells and hence low-level stress could improve pneumococcal survival. This implies that treatment with cell wall-active antibiotics results in damage to proteins. These changes in gene expression can be viewed as an attempt by the organism to defend it against the antibacterial activities of the agents. The molecular chaperone DnaK has been shown to be induced by a variety of stresses including cell wall-active antibiotic stress, suggesting its potential role in response of bacteria to stresses.

Pilus biogenesis and host pathogenesis
Colonization is not a single event but rather a dynamic process that involves panoply of changes in both the bacterium and host alike as a result of attachment. (Mulvey et al.,1998) have recently found during interactions between type 1-piliated E. coli and host superficial epithelial bladder cells glycoproteins, pili shortened to an average length of 0.12 to 0.01 mm compared to broth culture where they were 1 to 2 mm long. The mechanism by which this apparent shortening occurs remains unknown, but retraction of the pilus upon attachment has been suggested as one possible means (Mulvey et al., 1998). Scanning and high-resolution electron microscopy has shown that type 1 pili can mediate direct and intimate bacterial contact with the uroplakin coated bladder epithelium. Environmental conditions in the urinary tract presumably favor the expression of pili at critical points during the pathogenic cascade (Lim et al., 1998). Interestingly, pilus assembly leads to the activation of Cpx (extra cytoplasmic stress), which in turn would serve to reinforce the commitment to make pili by activating periplasmic assembly factors and maintaining the phase variation in ON state. This would ensure that daughter cells remain piliated in order to facilitate the colonization of the epithelium and persistence in the urinary tract. In addition, host–pathogen interactions in the urinary tract activate a cascade of innate defenses, such as an increase in the production of nitric oxide that may induce the periplasmic stresses (Mumtaz et al., 2000) and lead to an activation of Cpx. The activation of Cpx via pilus biogenesis and host–pathogen interactions serves to reinforce the commitment to produce pili, facilitating colonization of the urinary tract. In addition, Cpx may control the expression of a number of other virulence factors, putative CpxR binding sites upstream of genes encoding hemolysin, cytotoxic necrotizing factor and type 1 pili (Hung et al., 1996). Thus, environmental factors that activate pilus expression may indirectly activate additional virulence factors due to the induction of Cpx by OFF-pathway subunits. In this way, Cpx may tie up the expression of virulence factors to pilus biogenesis, which may be part of a mechanism in which microbial colonization is linked to the expression of new genes important in the pathogenic cascade and establishment in the host. The type 1 pilus adhesin FimH binds to mannose-containing receptors expressed by many host cell types and is a significant virulence determinant in the development of bladder infections (Thankavel, 1997). It has been shown that uropathogenic E. coli and K12 strains expressing type 1 pili can invade cultured human bladder epithelial cells, whereas nonpiliated strains or piliated strains lacking the FimH adhesin cannot. Thus, FimH may function like the invasin of Yersinia pseudotuberculosis and the internalin of Listeria monocytogenes (Parida, 1998). Once internalized, type 1-piliated E. coli cystitis isolates, but not their K12 counterparts, are able to proliferate and survive within the host cell. Thus the elucidation of the molecular mechanisms of pilus mediated bacterial attachment to host cells and the consequent pathogenesis offers the opportunity to develop new methods of prevention and treatment for many bacterial diseases.

Drug targeting based on the mechanism of the chaperone –usher system Strategies for inhibition of pilus biogenesis are based on three different points of the processes of pilus biogenesis and adhesion: inhibition of chaperone-subunit complex formation; inhibition of chaperone-subunit interaction with the usher; and inhibition of adhesion to the host receptor. P and type 1 pili are responsible for the early onset and persistence of UPEC-caused urinary tract infections (UTIs) by mediating attachment to the kidney epithelium (P pili) or attachment and invasion of the bladder epithelium cells (type 1 pili), respectively. They are assembled by the conserved chaperone/usher (CU) pathway, responsible for the biogenesis of more than 100 surface organelles in many other important human pathogens (Yersinia, Salmonella, Shigella, and Haemophilus). The activity of a family of bicyclic 2-pyridones, termed pilicides, was evaluated in two different pilus biogenesis systems in uropathogenic Escherichia coli. A group of antibacterial agents called ?pilicides? (pyridinones derivatives) was designed based on the crystallographic data of both PapD and FimC chaperones and their complexes (Svensson et al., 2001). Pilicides blocks the process of pilus biogenesis by binding to three possible binding sites in FimC or PapD. Inhibition of the latter interaction is particularly promising as it is the only one to have been convincingly established (Pinkner et al., 2006). Pilicides targeting this site, by inhibiting pilus biogenesis, have been shown to interfere with bacterial attachment and biofilm formation. Finally, anti-adhesive compounds targeted against the adhesive sub-units like antiadhesin antibodies have been shown to block bacterial adhesion (Langermann, 2000), thus paves the way to antimicrobial vaccine development strategies. Pilicides block pilus biogenesis by preventing chaperone-subunit complexes from interacting with the outer membrane usher (Pinkner et al., 2006). Rationally designed small compounds inhibit pilus biogenesis in uropathogenic bacteria. The crystal structure of a pilicidechaperone complex indicates that the pilicide binds to a conserved hydrophobic patch on strands F1, C1 and D1 on the back of the Nterminal domain of the pilus chaperone (Pinkner, et al.2006). So far, efforts at developing pilicides have focused on inhibiting the periplasmic chaperone proteins of the chaperone usher pathway in uropathogenic E. coli (UPEC). Bicyclic 2-pyridones and N-substituted amino acid derivatives have been shown to competitively inhibit binding of chaperones to pilin subunits by surface plasmon resonance (Svensson et al., 2001). In vitro, bicyclic 2- pyridones have also been shown to inhibit hemagglutination and biofilm formation in laboratory and clinical E. coli strains, and ex vivo they have been shown to inhibit adhesion of the bacteria to bladder carcinoma cells by 90%. It has been suggested that pilicides may have broad-spectrum of activity due to the conservation of both chaperone structure and the chaperone-usher pathway (Lee, et al., 2003).

This is suggested as an alternative and attractive approach to meet the vital needs in developing new anti infective agents. The pilicides were designed to mimic the C-terminal part of the fimbrial subunits and to bind to FimC or PapD thus blocking the chaperone from binding to the pilus subunits in the periplasm. Another interaction site of these pilicides has been shown to be at the surface of the chaperone involved in the interaction with the usher, thus blocking subunit delivery. In addition to rationally designed small synthetic molecules, natural compounds are also screened for their activity against adhesion. Proanthocyanidines, a component of cranberry juice represents one of the most well known natural products used to block adhesion of uropathogenic E. coli in the bladder. Coating of abiotic surfaces with isolated group II capsule polysaccharides of E. coli has been shown to drastically decrease adhesion and biofilm formation and may be used for new strategies to reduce biofilm formation on medical devices (Valle, 2006).

Heat shock protein as antibody triggers and potential vaccines:
Analysis of immune responses to bacteria in the 1970s enabled scientists to identify what was termed as ?common antigen? in many bacterial species. Patients infected with Mycobacterium tuberculosis or Mycobacterium leprae exhibits significant antibody responses to a 65-kDa antigen which was identified as the molecular chaperone Cpn60. It has now been established that a number of molecular chaperones from bacteria and protozoan parasites (Cpn60, Hsp70, and Hsp90) are (i) potent immunogens, (ii) active immunomodulators, and (iii) inducers of cross-reactive immunity and autoimmunity (Van Eden et al., 2005). The mammalian immune system recognizes the molecular chaperones of infecting parasites as strong immunological signals, which is surprising in view of the significant homology between host and parasite proteins. The Cpn60 (Hsp65) protein of M. tuberculosis has also proven to be an extremely powerful immunomodulator that is able to protect against a number of experimental autoimmune diseases in rodents, including diabetes. Members of the hsp70 family in other parasites and bacteria have proved to be immunogenic in both humans and experimental animals. For example, the hsp70 of Schistosoma mansoni shows about 85% homology with human hsp70, yet the majority of infected animals and humans develop antibodies to the S. mansoni protein (Hedstrom et al., 1987). The antibodies are directed towards the nonconserved sequences of the protein and can distinguished between infection with S. mansoni and that with S. japonicum (Scallon, 1987). Antibodies produced against malarial hsp70 proteins are directed mainly at nonconserved epitopes (Peterson, 1988), although a minor component also reacts with human hsp70 (24). Infection with Brugia malayi stimulates antihsp70 antibodies that react predominantly with epitopes specific to the Brugia protein, but there is some cross reactivity with hsp70 molecules from S. mansoni and Plasmodium falciparum (Selkrik et al., 1989). A 75-kDa protective antigen of Chlamydia trachomatis has also been identified as a member of the hsp70 family, and human antibodies react primarily with non conserved epitopes of the protein. Therefore, members of the hsp70 family from a wide range of parasites and bacteria are strong B-cell antigens, stimulating antibodies directed mainly towards the nonconserved regions of the protein. There is a variable degree of cross-reactivity with hsp70 proteins of other species and a minimal response to human hsp70, consistent with the need to preserve self tolerance. In the case of M. leprae hsp70, the dominant antibody response is directed to the C-terminal region. Hsp60 has been found to be a common antigen of many bacterial pathogens including species of Pseudomonas, Mycobacterium, Borrelia, Salmonella, Legionella, Coxiella and Rickettsia (Shinnick, 1991). In Borellia burgdorferi, there are two HSP60 of molecular masses 60 and 66 kDa which have been implicated in developing autoimmune pathologies such as arthritis (Carreiro et al 1990). HSP60 class of proteins serves as an immunodominant targets of α, ß and γ, δ classes of T-lymphocytes and have been used to provoke immunological protection against Mycobacterium and Legionella (Silva and Lowrie, 1994). It has been postulated that since HSP60 is highly conserved, the host may frequently encounter this antigen through infection with various other microorganisms there by constantly boosting the immune response to HSP (Kaufmann et al 1991). Chimeric pili/fimbriae with inserted antigenic sequences can be used as effective and safe recombinant vaccines, application of atypical fimbriae Saf for design of Salmonella vaccine components of the Salmonella atypical fimbriae (Saf) are investigated for inclusion in a Salmonella vaccine. Vaccination with purified Dr fimbriae reduces mortality associated with chronic urinary tract infection due to E. coli bearing Dr adhesin (Pawel Goluszko, 2005). Purified E. coli Dr fimbrial antigen to vaccinate C3H/HeJ mice against an experimental urinary tract infection due to a homologous strain bearing Dr adhesion had demonstrated reduced mortality in the vaccinated animals. Antipneumococcal DnaK antiserum did not cross react with DnaK homologues in E.coli, staphylococcus aureus and human cells and hence may be a good candidate as a vaccine (Hamel et al., 1997). Still, the role Dna K in pathogenesis remains unknown. The difference between gram positive, and gram negative bacteria, suggests that the regulation mechanism of heat shock response of gram positive bacteria (especially DnaK function of gram positive bacteria) is quite different than E.coli and other gram negative.

CONCLUSION
The new paradigm for antimicrobial therapy should redefine the goal of balance in favor of the host enabling to control infection, rather than complete in vivo killing of a pathogen by the drug itself. Though some virulence inhibitors such as pilicides and T3SS inhibitors have the potential to target a wider spectrum of bacteria, new approaches have to be designed to understand how bacteria cause disease. As antibiotic resistance continues to evolve and the need for new antimicrobials continues to grow therapeutics that target in vivo essential gene functions, all the more compelling. Pilicides, by blocking chaperone and usher functions, have the potential to inhibit pili formation in a broad spectrum of pathogenic bacteria to prevent critical host–pathogen interactions necessary for many diseases. There are hundreds of diverse cell-surface virulence organelles that are assembled by the chaperone–usher pathway in important bacterial pathogens. Because all chaperones have a conserved structure and mechanism of action, it is reasonable to propose that pilicides likely have broad-spectrum activity. These pilicides represent an example of selective, low-molecular-weight, nonpeptidic virulence-determinant inhibitors (Gauthier et al., 2005; Hung et al., 2005). Immunization with a FimH-based vaccine reduces bladder colonization by uropathogenic E. coli by 99% in a mouse cystitis model and suggested adhesinbased vaccines may be effective in preventing both urinary tract and other bacterial infections. Understanding the molecular events involved in the biogenesis of these organelles will be crucial for the development of novel therapeutic strategies. Elucidating common themes in these pathways will be a prerequisite for any efforts targeted towards developing a therapeutic strategy with broad-spectrum activity. Targeting bacterial virulence or disrupting the interaction between the host and the pathogen are attractive options and should be explored. The identification of those processes that occur following attachment will undoubtedly open up further avenues of therapeutic possibilities, as we come closer to understanding how hostpathogen interactions lead to the expression of bacterial genes that are important in pathogenesis. Besides having high sequence homology Hsps can be used as protective vaccines. The design of new drugs can be based on either mimicking the conformation of known ligands or on the structure of the peptide-binding domain of the receptor. The IgG repertoire during intravesical bacille Calmette- Guerin (BCG) immunotherapy in superficial bladder patients includes antibodies to GroEL and Hsp70 but not to DnaK (Zlotta et al., 1997) exploiting the functional differences between bacterial DnaK and the analogous human Hsp70. This finding emphasizes the significant structural and functional differences between mammalian Hsp70 and the corresponding bacterial DnaK and supports our findings and hypothesis that antibacterial peptides can inactivate DnaK (bacterial Hsp70) without binding to Hsp70 (human) and affecting its normal functions. Drosocin, pyrrhocoricin, and apidaecin, representing the short (18-20 amino acid residues) proline-rich antibacterial peptide family, originally isolated from insects, were shown to act on a target bacterial protein in a stereospecific manner. Radicicol represents the first non –benzoquninone ansamycin antifungal inhibitor of Hsp90. It is thus worth investing both effort and cost effective in antivirulence inhibitor research. In this effort, structural biology allied with improved computational tools provides a powerful platform for rational chemical design and thus, should help fulfill our antibiotics development goals in the very near future. In conclusion microorganisms have smartly harnessed utilization of host‘s unfavorable environment by several molecular mechanisms, increased induction of genes coding for stress proteins and deletion of these genes resulted in attenuation of their growth within the host. Inhibitions of these factors are attainable by pharmacological new lead compounds that function directly by binding and inhibiting HSPs are under clinical trials are cited in literatures.

ACKNOWLEDGEMENT
The author (R.B) thanks the Vice-Chancellor and Registrar of Periyar University for their support and encouragement while preparing the manuscript. Authors acknowledge the immense help received from the scholars whose articles are cited and included in references of this manuscript. The authors are also grateful to authors / editors / publishers of all those articles, journals and books from where the literature for this article has been reviewed and discussed. Competing interests: None declared. Sources of support: None.

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32. Parida, S.K., Domann, E., Rohde,M., Muller, S., Darji, A., Hain, T., Wehland, J., Chakraborty, T. 1998. Internalin B is essential for adhesion and mediates the invasion of Listeria monocytogenes into human endothelial cells. Mol Microbiol. 28:81-93.

33. Svensson, A., Larsson, A., Emtenas, H., Hedenstrom, M., Fex, T.,et al., 2001. Design and evaluation of pilicides: potential novel antibacterial agents directed against uropathogenic Escherichia coli. ChemBioChem. 2, 915.

34. Pinkner, J.S., Remaut, H., Buelens, F., Miller, E., Aberg, V. 2006. Rationally designed small compounds inhibit pilus biogenesis in uropathogenic bacteria. Proc. Natl. Acad. Sci. USA. 103:17897–17902.

35. Langermann, S., Mollby, R., Burlein, J. E., Palaszynski, S. R., Auguste, C. G. 2000. Vaccination with FimH adhesin protects cynomolgus monkeys from colonization and infection by uropathogenic Escherichia coli. J. Infect. Dis. 181, 774.

36. Lee, Y.M., Almqvist, F. and Hultgren, S.J. 2003. Targeting virulence for antimicrobial chemotherapy. Curr. Opin. Pharmacol. 3, 513–519.

37. Valle, J. ,Da Re, S., Henry, N., Fontaine, T., Balestrino, D., Latour-Lambert P., and Ghigo, J.M. 2006. Broad-spectrum biofilm inhibition by a secreted bacterial polysaccharide, Proc Natl Acad Sci U S A .103, 12558–12563.

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Announcements

Dr. Pramod Kumar Manjhi joined Editor-in-Chief since July 2021 onwards

COPE guidelines for Reviewers

SCOPUS indexing: 2014, 2019 to 2021


Awards, Research and Publication incentive Schemes by IJCRR

Best Article Award: 

One article from every issue is selected for the ‘Best Article Award’. Authors of selected ‘Best Article’ are rewarded with a certificate. IJCRR Editorial Board members select one ‘Best Article’ from the published issue based on originality, novelty, social usefulness of the work. The corresponding author of selected ‘Best Article Award’ is communicated and information of award is displayed on IJCRR’s website. Drop a mail to editor@ijcrr.com for more details.

Women Researcher Award:

This award is instituted to encourage women researchers to publish her work in IJCRR. Women researcher, who intends to publish her research work in IJCRR as the first author is eligible to apply for this award. Editorial Board members decide on the selection of women researchers based on the originality, novelty, and social contribution of the research work. The corresponding author of the selected manuscript is communicated and information is displayed on IJCRR’s website. Under this award selected women, the author is eligible for publication incentives. Drop a mail to editor@ijcrr.com for more details.

Emerging Researcher Award:

‘Emerging Researcher Award’ is instituted to encourage student researchers to publish their work in IJCRR. Student researchers, who intend to publish their research or review work in IJCRR as the first author are eligible to apply for this award. Editorial Board members decide on the selection of student researchers for the said award based on originality, novelty, and social applicability of the research work. Under this award selected student researcher is eligible for publication incentives. Drop a mail to editor@ijcrr.com for more details.


Best Article Award

A study by Dorothy Ebere Adimora et al. entitled \"Remediation for Effects of Domestic Violence on Psychological well-being, Depression and Suicide among Women During COVID-19 Pandemic: A Cross-cultural Study of Nigeria and Spain\" is awarded Best Article of Vol 14 issue 23
A study by Muhas C. et al. entitled \"Study on Knowledge & Awareness About Pharmacovigilance Among Pharmacists in South India\" is awarded Best article for Vol 14 issue 22
A study by Saurabh Suvidha entitled \"A Case of Mucoid Degeneration of Uterine Fibroid with Hydrosalphinx and Ovarian Cyst\" is awarded Best article of Vol 14 issue 21
A study by Alice Alice entitled \"Strengthening of Human Milk Banking across South Asian Countries: A Next Step Forward\" is awarded Best article of Vol 14 issue 20
A study by Sathyanarayanan AR et al. entitled \"The on-task Attention of Individuals with Autism Spectrum Disorder-An Eye Tracker Study Using Auticare\" is awarded Best article of Vol 14 issue 19
A study by Gupta P. et al. entitled \"A Short Review on \"A Novel Approach in Fast Dissolving Film & their Evaluation Studies\" is awarded Best Article of Vol 14 issue 18.
A study by Shafaque M. et al. entitled \"A Case-Control Study Performed in Karachi on Inflammatory Markers by Ciprofloxacin and CoAmoxicillin in Patients with Chronic Suppurative Otitis Media\" is awarded Best Article of Vol 14 issue 17
A study by Ali Nawaz et al. entitled \"A Comparative Study of Tubeless versus Standard Percutaneous Nephrolithotomy (PCNL) \? A Randomized Controlled Study\" is awarded Best Article for Vol 14 issue 16.
A study by Singh R. et al. entitled \"A Prospective Study to Find the Association of Astigmatism in Patients of Vernal Keratoconjunctivitis (VKC) in a Tertiary Health Care Centre in India (Vindhya Region MP)\" is awarded Best Article for Vol 14 issue 15
A Study by Humaira Tahir et al. entitled "Comparison of First Analgesic Demand after Major Surgeries of Obstetrics and Gynecology between Pre-Emptive Versus Intra-Operative Groups by Using Intravenous Paracetamol: A Cross-Sectional Study" is awarded Best Article for Vol 14 issue 14
A Study by Monica K. entitled "Risk Predictors for Lymphoma Development in Sjogren Syndrome - A Systematic Review" is awarded Best Article for Vol 14 issue 13
A Study by Mokhtar M Sh et al. entitled "Prevalence of Hospital Mortality of Critically Ill Elderly Patients" is awarded Best Article for Vol 14 issue 12
A Study by Vidya S. Bhat et al. entitled "Effect of an Indigenous Cleanser on the Microbial Biofilm on Acrylic Denture Base - A Pilot Study" is awarded Best Article for Vol 14 issue 11
A Study by Pandya S. et al. entitled "Acute and 28-Day Repeated Dose Subacute Toxicological Evaluation of Coroprotect Tablet in Rodents" is awarded Best Article for Vol 14 issue 10
A Study by Muhammad Zaki et al. entitled "Effect of Hemoglobin Level on the Severity of Acute Bronchiolitis in Children: A Case-Control Study" is awarded Best Article for Vol 14 issue 09
A Study by Vinita S & Ayushi S entitled "Role of Colour Doppler and Transvaginal Sonography for diagnosis of endometrial pathology in women presenting with Abnormal Uterine Bleeding" is awarded Best Article for Vol 14 issue 08
A Study by Prabhu A et al. entitled "Awareness of Common Eye Conditions among the ASHA (Accredited Social Health Activist) Workers in the Rural Communities of Udupi District- A Pilot Study" is awarded Best Article for Vol 14 issue 07
A Study by Divya MP et al. entitled "Non-Echoplanar Diffusion-Weighted Imaging and 3D Fiesta Magnetic Resonance Imaging Sequences with High Resolution Computed Tomography Temporal Bone in Assessment and Predicting the Outcome of Chronic Suppurative Otitis Media with Cholesteatoma" is awarded Best Article for Vol 14 issue 06
A Study by Zahoor Illahi Soomro et al. entitled "Functional Outcomes of Fracture Distal Radius after Fixation with Two Different Plates: A Retrospective Comparative Study" is awarded Best Article for Vol 14 issue 05
A Study by Ajai KG & Athira KN entitled "Patients’ Gratification Towards Service Delivery Among Government Hospitals with Particular Orientation Towards Primary Health Centres" is awarded Best Article for Vol 14 issue 04
A Study by Mbungu Mulaila AP et al. entitled "Ovarian Pregnancy in Kindu City, D.R. Congo - A Case Report" is awarded Best Article for Vol 14 issue 03
A Study by Maryam MJ et al. entitled "Evaluation Serum Chemerin and Visfatin Levels with Rheumatoid Arthritis: Possible Diagnostic Biomarkers" is awarded Best Article for Vol 14 issue 02
A Study by Shanthan KR et al. entitled "Comparison of Ultrasound Guided Versus Nerve Stimulator Guided Technique of Supraclavicular Brachial Plexus Block in Patients Undergoing Upper Limb Surgeries" is awarded Best Article for Vol 14 issue 01
A Study by Amol Sanap et al. entitled "The Outcome of Coxofemoral Bypass Using Cemented Bipolar Hemiarthroplasty in the Treatment of Unstable Intertrochanteric Fracture of Femur in a Rural Setup" is awarded Best Article Award of Vol 13 issue 24
A Study by Manoj KP et al. entitled "A Randomized Comparative Clinical Trial to Know the Efficacy of Ultrasound-Guided Transversus Abdominis Plane Block Against Multimodal Analgesia for Postoperative Analgesia Following Caesarean Section" is awarded Best Article Award of Vol 13 issue 23
A Study by Karimova II et al. entitled "Changes in the Activity of Intestinal Carbohydrases in Alloxan-Induced Diabetic Rats and Their Correction with Prenalon" is awarded Best Article of Vol 13 issue 22
A Study by Ashish B Roge et al. entitled "Development, Validation of RP-HPLC Method and GC MS Analysis of Desloratadine HCL and It’s Degradation Products" is awarded Best Article of Vol 13 issue 21
A Study by Isha Gaurav et al. entitled "Association of ABO Blood Group with Oral Cancer and Precancer – A Case-control Study" is awarded Best Article for Vol 13 issue 20
A Study by Amr Y. Zakaria et al. entitled "Single Nucleotide Polymorphisms of ATP-Binding Cassette Gene(ABCC3 rs4793665) affect High Dose Methotrexate-Induced Nephrotoxicity in Children with Osteosarcoma" is awarded Best Article for Vol 13 issue 19
A Study by Kholis Ernawati et al. entitled "The Utilization of Mobile-Based Information Technology in the Management of Dengue Fever in the Community Year 2019-2020: Systematic Review" is awarded Best Article for Vol 13 issue 18
A Study by Bhat Asifa et al. entitled "Efficacy of Modified Carbapenem Inactivation Method for Carbapenemase Detection and Comparative Evaluation with Polymerase Chain Reaction for the Identification of Carbapenemase Producing Klebsiella pneumonia Isolates" is awarded Best Article for Vol 13 issue 17
A Study by Gupta R. et al. entitled "A Clinical Study of Paediatric Tracheostomy: Our Experience in a Tertiary Care Hospital in North India" is awarded Best Article for Vol 13 issue 16
A Study by Chandran Anand et al. entitled "A Prospective Study on Assessment of Quality of Life of Patients Receiving Sorafenib for Hepatocellular Carcinoma" is awarded Best article for Vol 13 issue 15
A Study by Rosa PS et al. entitled "Emotional State Due to the Covid – 19 Pandemic in People Residing in a Vulnerable Area in North Lima" is awarded Best Article for Vol 13 issue 14
A Study by Suvarna Sunder J et al. entitled "Endodontic Revascularization of Necrotic Permanent Anterior Tooth with Platelet Rich Fibrin, Platelet Rich Plasma, and Blood Clot - A Comparative Study" is awarded Best Article for Vol 13 issue 13
A Study by Mona Isam Eldin Osman et al. entitled "Psychological Impact and Risk Factors of Sexual Abuse on Sudanese Children in Khartoum State" is awarded Best Article for Vol 13 issue 12
A Study by Khaw Ming Sheng & Sathiapriya Ramiah entitled "Web Based Suicide Prevention Application for Patients Suffering from Depression" is awarded Best Article for Vol 13 issue 11
A Study by Purushottam S. G. et al. entitled "Development of Fenofibrate Solid Dispersions for the Plausible Aqueous Solubility Augmentation of this BCS Class-II Drug" is awarded Best article for Vol 13 issue 10
A Study by Kumar S. et al. entitled "A Study on Clinical Spectrum, Laboratory Profile, Complications and Outcome of Pediatric Scrub Typhus Patients Admitted to an Intensive Care Unit from a Tertiary Care Hospital from Eastern India" is awarded Best Article for Vol 13 issue 09
A Study by Mardhiah Kamaruddin et al. entitled "The Pattern of Creatinine Clearance in Gestational and Chronic Hypertension Women from the Third Trimester to 12 Weeks Postpartum" is awarded Best Article for Vol 13 issue 08
A Study by Sarmila G. B. et al. entitled "Study to Compare the Efficacy of Orally Administered Melatonin and Clonidine for Attenuation of Hemodynamic Response During Laryngoscopy and Endotracheal Intubation in Gastrointestinal Surgeries" is awarded Best Article for Vol 13 issue 07
A Study by M. Muthu Uma Maheswari et al. entitled "A Study on C-reactive Protein and Liver Function Tests in Laboratory RT-PCR Positive Covid-19 Patients in a Tertiary Care Centre – A Retrospective Study" is awarded Best Article of Vol 13 issue 06 Special issue Modern approaches for diagnosis of COVID-19 and current status of awareness
A Study by Gainneos PD et al. entitled "A Comparative Evaluation of the Levels of Salivary IgA in HIV Affected Children and the Children of the General Population within the Age Group of 9 – 12 Years – A Cross-Sectional Study" is awarded Best Article of Vol 13 issue 05 Special issue on Recent Advances in Dentistry for better Oral Health
A Study by Alkhansa Mahmoud et al. entitled "mRNA Expression of Somatostatin Receptors (1-5) in MCF7 and MDA-MB231 Breast Cancer Cells" is awarded Best Article of Vol 13 issue 06
A Study by Chen YY and Ghazali SRB entitled "Lifetime Trauma, posttraumatic stress disorder Symptoms and Early Adolescence Risk Factors for Poor Physical Health Outcome Among Malaysian Adolescents" is awarded Best Article of Vol 13 issue 04 Special issue on Current Updates in Plant Biology to Medicine to Healthcare Awareness in Malaysia
A Study by Kumari PM et al. entitled "Study to Evaluate the Adverse Drug Reactions in a Tertiary Care Teaching Hospital in Tamilnadu - A Cross-Sectional Study" is awarded Best Article for Vol 13 issue 05
A Study by Anu et al. entitled "Effectiveness of Cytological Scoring Systems for Evaluation of Breast Lesion Cytology with its Histopathological Correlation" is awarded Best Article of Vol 13 issue 04
A Study by Sharipov R. Kh. et al. entitled "Interaction of Correction of Lipid Peroxidation Disorders with Oxibral" is awarded Best Article of Vol 13 issue 03
A Study by Tarek Elwakil et al. entitled "Led Light Photobiomodulation Effect on Wound Healing Combined with Phenytoin in Mice Model" is awarded Best Article of Vol 13 issue 02
A Study by Mohita Ray et al. entitled "Accuracy of Intra-Operative Frozen Section Consultation of Gastrointestinal Biopsy Samples in Correlation with the Final Histopathological Diagnosis" is awarded Best Article for Vol 13 issue 01
A Study by Badritdinova MN et al. entitled "Peculiarities of a Pain in Patients with Ischemic Heart Disease in the Presence of Individual Combines of the Metabolic Syndrome" is awarded Best Article for Vol 12 issue 24
A Study by Sindhu Priya E S et al. entitled "Neuroprotective activity of Pyrazolone Derivatives Against Paraquat-induced Oxidative Stress and Locomotor Impairment in Drosophila melanogaster" is awarded Best Article for Vol 12 issue 23
A Study by Habiba Suhail et al. entitled "Effect of Majoon Murmakki in Dysmenorrhoea (Usre Tams): A Standard Controlled Clinical Study" is awarded Best Article for Vol 12 issue 22
A Study by Ghaffar UB et al. entitled "Correlation between Height and Foot Length in Saudi Population in Majmaah, Saudi Arabia" is awarded Best Article for Vol 12 issue 21
A Study by Siti Sarah Binti Maidin entitled "Sleep Well: Mobile Application to Address Sleeping Problems" is awarded Best Article for Vol 12 issue 20
A Study by Avijit Singh"Comparison of Post Operative Clinical Outcomes Between “Made in India” TTK Chitra Mechanical Heart Valve Versus St Jude Mechanical Heart Valve in Valve Replacement Surgery" is awarded Best Article for Vol 12 issue 19
A Study by Sonali Banerjee and Mary Mathews N. entitled "Exploring Quality of Life and Perceived Experiences Among Couples Undergoing Fertility Treatment in Western India: A Mixed Methodology" is awarded Best Article for Vol 12 issue 18
A Study by Jabbar Desai et al. entitled "Prevalence of Obstructive Airway Disease in Patients with Ischemic Heart Disease and Hypertension" is awarded Best Article for Vol 12 issue 17
A Study by Juna Byun et al. entitled "Study on Difference in Coronavirus-19 Related Anxiety between Face-to-face and Non-face-to-face Classes among University Students in South Korea" is awarded Best Article for Vol 12 issue 16
A Study by Sudha Ramachandra & Vinay Chavan entitled "Enhanced-Hybrid-Age Layered Population Structure (E-Hybrid-ALPS): A Genetic Algorithm with Adaptive Crossover for Molecular Docking Studies of Drug Discovery Process" is awarded Best article for Vol 12 issue 15
A Study by Varsha M. Shindhe et al. entitled "A Study on Effect of Smokeless Tobacco on Pulmonary Function Tests in Class IV Workers of USM-KLE (Universiti Sains Malaysia-Karnataka Lingayat Education Society) International Medical Programme, Belagavi" is awarded Best article of Vol 12 issue 14, July 2020
A study by Amruta Choudhary et al. entitled "Family Planning Knowledge, Attitude and Practice Among Women of Reproductive Age from Rural Area of Central India" is awarded Best Article for special issue "Modern Therapeutics Applications"
A study by Raunak Das entitled "Study of Cardiovascular Dysfunctions in Interstitial Lung Diseas epatients by Correlating the Levels of Serum NT PRO BNP and Microalbuminuria (Biomarkers of Cardiovascular Dysfunction) with Echocardiographic, Bronchoscopic and HighResolution Computed Tomography Findings of These ILD Patients" is awarded Best Article of Vol 12 issue 13 
A Study by Kannamani Ramasamy et al. entitled "COVID-19 Situation at Chennai City – Forecasting for the Better Pandemic Management" is awarded best article for  Vol 12 issue 12
A Study by Muhammet Lutfi SELCUK and Fatma entitled "Distinction of Gray and White Matter for Some Histological Staining Methods in New Zealand Rabbit's Brain" is awarded best article for  Vol 12 issue 11
A Study by Anamul Haq et al. entitled "Etiology of Abnormal Uterine Bleeding in Adolescents – Emphasis Upon Polycystic Ovarian Syndrome" is awarded best article for  Vol 12 issue 10
A Study by entitled "Estimation of Reference Interval of Serum Progesterone During Three Trimesters of Normal Pregnancy in a Tertiary Care Hospital of Kolkata" is awarded best article for  Vol 12 issue 09
A Study by Ilona Gracie De Souza & Pavan Kumar G. entitled "Effect of Releasing Myofascial Chain in Patients with Patellofemoral Pain Syndrome - A Randomized Clinical Trial" is awarded best article for  Vol 12 issue 08
A Study by Virendra Atam et. al. entitled "Clinical Profile and Short - Term Mortality Predictors in Acute Stroke with Emphasis on Stress Hyperglycemia and THRIVE Score : An Observational Study" is awarded best article for  Vol 12 issue 07
A Study by K. Krupashree et. al. entitled "Protective Effects of Picrorhizakurroa Against Fumonisin B1 Induced Hepatotoxicity in Mice" is awarded best article for issue Vol 10 issue 20
A study by Mithun K.P. et al "Larvicidal Activity of Crude Solanum Nigrum Leaf and Berries Extract Against Dengue Vector-Aedesaegypti" is awarded Best Article for Vol 10 issue 14 of IJCRR
A study by Asha Menon "Women in Child Care and Early Education: Truly Nontraditional Work" is awarded Best Article for Vol 10 issue 13
A study by Deep J. M. "Prevalence of Molar-Incisor Hypomineralization in 7-13 Years Old Children of Biratnagar, Nepal: A Cross Sectional Study" is awarded Best Article for Vol 10 issue 11 of IJCRR
A review by Chitra et al to analyse relation between Obesity and Type 2 diabetes is awarded 'Best Article' for Vol 10 issue 10 by IJCRR. 
A study by Karanpreet et al "Pregnancy Induced Hypertension: A Study on Its Multisystem Involvement" is given Best Paper Award for Vol 10 issue 09

List of Awardees

A Study by Ese Anibor et al. "Evaluation of Temporomandibular Joint Disorders Among Delta State University Students in Abraka, Nigeria" from Vol 13 issue 16 received Emerging Researcher Award


A Study by Alkhansa Mahmoud et al. entitled "mRNA Expression of Somatostatin Receptors (1-5) in MCF7 and MDA-MB231 Breast Cancer Cells" from Vol 13 issue 06 received Emerging Researcher Award


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Disclaimer: International Journal of Current Research and Review (IJCRR) provides platform for researchers to publish and discuss their original research and review work. IJCRR can not be held responsible for views, opinions and written statements of researchers published in this journal.



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International Journal of Current Research and Review (IJCRR) provides platform for researchers to publish and discuss their original research and review work. IJCRR can not be held responsible for views, opinions and written statements of researchers published in this journal

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