Treatment to common bacterial infections are becoming ineffective of late, owing to the emergence and dissemination of antibiotic resistance globally. Escherichia coli and Klebsiella pneumoniae are ...the most notorious microorganisms and are among the critical priority pathogens listed by WHO in 2017. These pathogens are the predominant cause of sepsis, urinary tract infections (UTIs), pneumonia, meningitis and pyogenic liver abscess. Concern arises due to the resistance of bacteria to most of the beta lactam antibiotics like penicillin, cephalosporin, monobactams and carbapenems, even to the last resort antibiotics like colistin. Preventing influx by modulation of porins, extruding the antibiotics by overexpression of efflux pumps, mutations of drug targets/receptors, biofilm formation, altering the drug molecules and rendering them ineffective are few resistance mechanisms that are adapted by Enterobacteriaeceae upon exposure to antibiotics. The situation is exacerbated due to the process of horizontal gene transfer (HGT), wherein the genes encoding resistance mechanisms are transferred to the neighbouring bacteria through plasmids/phages/uptake of free DNA. Carbapenemases, other beta lactamases and mcr genes coding for colistin resistance are widely disseminated leading to limited/no therapeutic options against those infections. Development of new antibiotics can be viewed as a possible solution but it involves major investment, time and labour despite which, the bacteria can easily adapt to the new antibiotic and evolve resistance in a relatively short time. Targeting the resistance mechanisms can be one feasible alternative to tackle these multidrug resistant (MDR) pathogens. Removal of plasmid (plasmid curing) causing resistance, use of bacteriophages and bacteriotherapy can be other potential approaches to combat infections caused by MDR E. coli and K. pneumoniae. The present review discusses the efficacies of these therapies in mitigating these infections, which can be potentially used as an adjuvant therapy along with existing antibiotics.
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
•Fabricating AgNPs integrated ZnO nanoplates via wet chemical method.•Efficient sun light mediated degradation of textile dyes.•Effective mitigation of E.coli biofilms.•AgNPs concentration dependent ...photocatalytic and anti-biofilm activity.
Plasmonic silver nanoparticles (AgNPs) doped ZnO (Ag-ZnO) nanoplates were synthesized by simple wet chemical method in presence of hexylamine with an intent to improve the visible light mediated photocatalytic activity of ZnO. Powder X-ray diffraction (PXRD) analysis confirmed the integration of AgNPs with ZnO nanoplates. High-resolution transmission electron microscopic (HR-TEM) and X-ray photoelectron spectroscopy (XPS) analysis confirmed the formation of ZnO nanoplates and AgNPs doping. The concentration of Ag in ZnO nanoplates was increased by increasing hexylamine concentration. Ag-ZnO hybrid nanoplates exhibited efficient degradation of organic dyes (methyl orange (MO), methylene blue (MB), Eosin Y (EY) and rhodamine B (RB)) in presence of sun light compared to the pristine ZnO. Further, AgNPs doping with ZnO strongly enhanced anti-biofilm activity and showed strong prevention of colonization. The increase of AgNPs concentration in ZnO nanoplates exhibited enhancement of both photocatalytic and anti-biofilm activity that might be attributed to the improved light absorption in the visible region.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Infections by multidrug resistant bacteria (MDR) are becoming increasingly difficult to treat and alternative approaches like phage therapy, which is unhindered by drug resistance, are urgently ...needed to tackle MDR bacterial infections. During phage therapy phage cocktails targeting different receptors are likely to be more effective than monophages. In the present study, phages targeting carbapenem resistant clinical isolate of E. coli U1007 was isolated from Ganges River (U1G), Cooum River (CR) and Hospital waste water (M). Capsid architecture discerned using TEM identified the phage families as Podoviridae for U1G, Myoviridae for CR and Siphoviridae for M phage. Genome sequencing showed the phage genomes varied in size U1G (73,275 bp) CR (45,236 bp) and M (45,294 bp). All three genomes lacked genes encoding tRNA sequence, antibiotic resistant or virulent genes. A machine learning (ML) based multi-class classification model using Random Forest, Logistic Regression, and Decision Tree were employed to predict the host receptor targeted by receptor binding protein of all 3 phages and the best performing algorithm Random Forest predicted LPS O antigen, LamB or OmpC for U1G; FhuA, OmpC for CR phage; and FhuA, LamB, TonB or OmpF for the M phage. OmpC was validated as receptor for U1G by physiological experiments. In vivo intramuscular infection study in zebrafish showed that cocktail of dual phages (U1G + M) along with colsitin resulted in a significant 3.5 log decline in cell counts. Our study highlights the potential of ML tool to predict host receptor and proves the utility of phage cocktail to restrict E. coli U1007 in vivo.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Purified glycosides, Isoquercetin and Cassinopin from Crotalaria candicans were selected for the synthesis of biogenic copper nanoparticles (CuNPs).The designed biogenic CuNPs was characterized and ...when evaluated against panel of gram negative and positive bacteria, the biogenic CuNPs were found to be more effective against methicillin resistant Staphylococcus aureus (MRSA). Antibacterial, anti-biofilm effects and time kill studies confirmed the ability of biogenic CuNPs to curtail MRSA. Scanning electron microscopy, Crystal violet staining and fluorescent live-dead imaging showed that treatment with sub lethal levels of glycoside capped CuNPs resulted in greater than 50% decline in biofilm formation by MRSA, which implies that anti-biofilm effect of biogenic CuNPs is not dependent on antibacterial effect. Alizarin red assay implied that prolonged treatment of biogenic CuNPs in presence of MRSA, releases Cu(II) ions and hence antibiofilm effect is primarily mediated by NP and is not due to released Cu(II) ion. The NPs caused altered membrane permeability and reduced surface hydrophobicity, thus accounting for its antibiofilm effect.
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•Cassinopin and Isoquercetin capped biogenic copper nanoparticles (ISQ/CAS@CuNPs) were synthesized and characterized.•Live/Dead and SEM imaging showed that biogenic ISQ/CAS@CuNPs at sub MIC levels reduced surface colonization, inhibited MRSA biofilms.•ISQ/CAS@CuNPs showed significant reduction in MRSA cell surface hydrophobicity attenuating its abiotic adherence ability.•Cell membrane permeability assay imply membrane permeabilizing effect caused by ISQ/CAS@CuNPs was comparable with CTAB.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Antibiotics like colistin are the last resort to deal with infections by carbapenem-resistant Enterobacteriaceae (CREB). Resistance to colistin severely restricts therapeutic options. To tackle this ...dire situation, urgent measures to restore colistin sensitivity are needed. In this study, whole-genome sequencing of colistin-resistant E. coli strain was performed and the genome analysis revealed that the strain belonged to the sequence type ST405. Multiple mutations were observed in genes implicated in colistin resistance, especially those related to the L-Ara-4-N pathway but mgrB was unmutated and mcr1-9 genes were missing. MarR inhibitor salicylate was used to re-sensitize this strain to colistin, which increased the negative charge on the cell surface especially in colistin resistant E. coli (U3790 strain) and thereby facilitated a decrease in colistin MIC by 8 fold. It is indeed well known that MarR inhibition by salicylate triggers the expression of AcrAB efflux pumps through MarA. So, in order to fully restore colistin sensitivity, a potent efflux pump inhibitor (BC1), identified earlier by this group was employed. The combination of colistin with both salicylate and BC1 caused a remarkable 6 log reduction in cell counts of U3790 in time-kill assay. Infection of muscle tissue of zebrafish with U3790 followed by various treatments showed that the combination of colistin + salicylate + BC1 was highly effective in reducing bioburden in infected muscle tissue by 4 log fold. Thus, our study shows that a combination of MarR inhibitor to enhance colistin binding and efflux pump inhibitor to reduce colistin extrusion was highly effective in restoring colistin sensitivity in colistin-resistant clinical isolate of E. coli in vitro and in vivo.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Bacteriophages are a promising alternative for curtailing infections caused by multi drug resistant (MDR) bacteria. The objective of the present study is to evaluate phage populations from water ...bodies to inhibit planktonic and biofilm mode of growth of drug resistant
Klebsiella pneumoniae
in vitro and curtail planktonic growth in vivo in a zebrafish model. Phage specific to
K. pneumoniae
(MTCC 432) was isolated from Ganges River (designated as KpG). One-step growth curve, in vitro time kill curve study and in vivo infection model were performed to evaluate the ability of phage to curtail planktonic growth. Crystal violet assay and colony biofilm assay were performed to determine the action of phages on biofilms. KpG phages had a greater burst size, better bactericidal potential and enhanced inhibitory effect against biofilms formed at liquid air and solid air interfaces. In vitro time kill assay showed a 3 log decline and a 6 log decline in
K. pneumoniae
colony counts, when phages were administered individually and in combination with streptomycin, respectively. In vivo injection of KpG phages revealed that it did not pose any toxicity to zebrafish as evidenced by liver/brain enzyme profiles and by histopathological analysis. The muscle tissue of zebrafish, infected with
K. pneumoniae
and treated with KpG phages alone and in combination with streptomycin showed a significant 77.7% and 97.2% decline in CFU/ml, respectively, relative to untreated control. Our study reveals that KpG phages has the potential to curtail plantonic and biofilm mode of growth in higher animal models.
Highlights • Current state of knowledge on the MHC class I antigen processing pathway. • Molecular and immunological consequences of deficiency in ERAAP. • Mechanisms for detecting ERAAP-dysfunction. ...• Future perspectives.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Purified plant nutraceuticals afzelin and quercetrin from an edible plant- Crotolaria tetragona was employed for the fabrication of silver nanoparticles (AgNPs) by a sunlight mediated process. From ...among a panel of strains tested, AgNPs displayed potent bacteriostatic and bactericidal effect against P. aeruginosa and S. Typhi. Time kill studies revealed green synthesized AgNPs displayed comparable bactericidal effect with chemically synthesized AgNPs against S. Typhi. Antibiofilm potential of AgNPs showed that they were highly effective at sub MIC concentrations in causing 50% biofilm inhibition against food borne pathogen S. Typhi implying that antibiofilm effect is independent of antibacterial effect, which was evidenced by fluorescent imaging and SEM imaging. Mechanistic studies revealed that reduced cell surface hydrophobicity, decreased surface adherence, loss of membrane potential contributed to antibiofilm potential of afzelin/quercetrin AgNPs. Green synthesized afzelin/quercetrin AgNPs were also relatively less toxic and more effective in curtailing bioburden of S. Typhi in infected zebrafish by > 3 log fold. Ability of sunlight reduced afzelin/quercetrin NPs to mitigate planktonic mode of growth in vitro and in vivo and curtail biofilm formation of S. Typhi in vitro demonstrates its potential to curtail food borne pathogen in planktonic and biofilm mode of growth.
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•Nutraceuticals afzelin and quercetrin capped silver nanoparticles (AgNPs) were synthesized and characterized through UV, and TEM analysis.•Time kill studies revealed AgNPs displayed comparable bactericidal effect against S. Typhi.•AgNPs were highly effective at sub MIC concentrations in causing 50% biofilm inhibition against S. Typhi implying that antibiofilm effect is independent of antibacterial effect, as evidenced by fluorescent imaging and SEM imaging.•Mechanistic studies revealed that reduced cell surface hydrophobicity, decreased surface adherence, loss of membrane potential contributed to antibiofilm potential of afzelin/quercetrin AgNPs.•Afzelin/quercetrin AgNPs were also relatively less toxic and more effective in curtailing bioburden of S. Typhi in infected zebrafish by > 3 log fold.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Colistin resistance in
Enterobacteriaceae
especially
Klebsiella pneumoniae
and
Escherichia coli
is driving the evolution of pan drug resistant strains. Screening a library of 13 plant nutraceuticals ...led to the identification of acetyl shikonin and ursolic acid, which exhibited synergy with colistin against extremely drug resistant (XDR) clinical strains of
E. coli
(U3790) and
K. pneumoniae
(BC936). Ursolic acid caused a significant colistin MIC reversal of 16-fold in U3790 and 4-fold in BC936 strains. Ursolic acid also potentiated the bactericidal effect of colistin against both U3790 and BC936 by causing ~ 4 to 4.5 log fold decline in CFU of both clinical isolates in a time kill assay. At 2× minimum effective concentration, ursolic acid was non-toxic to zebrafish as evidenced by brain and liver enzyme profiles and by histopathology studies. In combination with colistin, ursolic acid reduced bacterial bioburden of U3790/BC936 by 1–1.58 log fold from the infected muscle tissue of zebrafish. Mechanistic explorations via studies on real time efflux, membrane potential and intracellular accumulation of dansyl chloride tagged colistin revealed that colistin efflux is inhibited by ursolic acid. In addition, ursolic acid also enhanced outer membrane permeability which probably facilitates colistin’s attack on outer and inner membranes. Our study shows that ursolic acid synergizes with colistin by inhibiting colistin efflux in
Enterobacteriaceae
that helps to curtail colistin resistant
Enterobacteriaceae
.
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•Synthesis of new water soluble Cu(II) complexes with NNN pincer type ligands.•Confirmation of structure and coordination geometries by single crystal x-ray analysis.•Relatively ...strong antibiofilm activities of the complexes against ESKAPE pathogens.•Molecular docking studies were performed for understanding the mechanism.
Bacteria in biofilms exhibited higher resistance to immune system and antibiotic treatment compared to their free living/planktonic counterparts. Hence there is a strong interest for developing new compounds with good antibiofilm activity. Herein three new Cu(II) complexes (CuL1, CuL2 and CuL3) with NNN pincer type ligands (L1-L3) were synthesized and the structures were confirmed by FT-IR, UV–Vis spectroscopy and single crystal X-ray analysis. Structural studies revealed the formation of five coordinate Cu(II) complexes with square-pyramidal geometry. All three compounds were investigated for antibiofilm activity against ESKAPE pathogens, such as Klebsiella pneumoniae, Enterococcus faecium, Acinetobacter baumanii, Pseudomonas aeruginosa, Enterobacter cloacae and Escherichia coli. Antibiofilm studies revealed that CuL1 was more effective against gram positive bacteria whereas CuL3 was more effective against gram negative bacteria. CuL2 showed least effective against all the bacteria stains. Computational docking studies of complexes with biomolecular targets revealed preferential binding with 5FCA (Enterococcus faecium).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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