Sibhghatulla Shaikh

Antibiotic resistance and extended spectrum beta-lactamases: Types, epidemiology and treatment

Antibiotic resistance is a problem of deep scientific concern both in hospital and community settings. Rapid detection in clinical laboratories is essential for the judicious recognition of antimicrobial resistant organisms. Production of extended-spectrum β-lactamases (ESBLs) is a significant resistance-mechanism that impedes the antimicrobial treatment of infections caused by Enterobacteriaceae and is a serious threat to the currently available antibiotic armory. ESBLs are classified into several groups according to their amino acid sequence homology. Proper infection control practices and barriers are essential to prevent spread and outbreaks of ESBL producing bacteria. As bacteria have developed different strategies to counter the effects of antibiotics, the identification of the resistance mechanism may help in the discovery and design of new antimicrobial agents. The carbapenems are widely regarded as the drugs of choice for the treatment of severe infections caused by ESBL-producing Enterobacteriaceae, although comparative clinical trials are scarce. Hence, more expeditious diagnostic testing of ESBL-producing bacteria and the feasible modification of guidelines for community-onset bacteremia associated with different infections are prescribed.

Role of anti-diabetic drugs as therapeutic agents in Alzheimer's disease

Recent data have suggested a strong possible link between Type 2 Diabetes Mellitus and Alzheimers disease (AD), although exact mechanisms linking the two are still a matter of research and debate. Interestingly, both are diseases with high incidence and prevalence in later years of life. The link appears so strong that some scientists use Alzheimers and Type 3 Diabetes interchangeably. In depth study of recent data suggests that the anti diabetic drugs not only have possible role in treatment of Alzheimers but may also arrest the declining cognitive functions associated with it. The present review gives an insight into the possible links, existing therapeutics and clinical trials of anti diabetic drugs in patients suffering from AD primarily or as co-morbidity. It may be concluded that the possible beneficial effects and usefulness of the current anti diabetic drugs in AD cannot be neglected and further research is required to achieve positive results. Currently, several drug trials are in progress to give conclusive evidence based data.

Forxiga (dapagliflozin): Plausible role in the treatment of diabetes‐associated neurological disorders

Numerous clinical and epidemiological studies have provided direct evidence to strengthen the link between type 2 diabetes (T2D) and Alzheimers disease (AD). The possibility that T2D patients might be at increased risk in developing AD has serious societal implications. Sodium glucose co‐transporter 2 (SGLT2) is one of the best targets in the treatment of diabetes, whereas acetylcholinesterase (AChE) has long been regarded as a therapeutic target for AD. This study explores the molecular interactions between AChE and SGLT2 with a new US Food and Drug Administration approved antidiabetic drug Forxiga (dapagliflozin) to explore a possible link between the treatments of AD and diabetes. Docking study was performed using “Autodock4.2.” Hydrophobic and cation–π interactions play an important role in the correct positioning of dapagliflozin within the catalytic site (CAS) of SGLT2 and AChE enzymes to permit docking. Free energy of binding (ΔG) of “dapagliflozin–SGLT2” and “dapagliflozin–CAS domain of AChE” interactions was found to be –6.25 and –6.28 kcal/mol, respectively. Hence, dapagliflozin might act as a potent dual inhibitor of SGLT2 and AChE. The results described herein may form the basis of future dual therapy against diabetes‐associated neurological disorders.

Synthesis and Characterization of Cefotaxime Conjugated Gold Nanoparticles and Their Use to Target Drug-Resistant CTX-M-Producing Bacterial Pathogens

Multidrug‐resistance due to “β lactamases having the expanded spectrum” (ESBLs) in members of Enterobacteriaceae is a matter of continued clinical concern. CTX‐M is among the most common ESBLs in Enterobacteriaceae family. In the present study, a nanoformulation of cefotaxime was prepared using gold nanoparticles to combat drug‐resistance in ESBL producing strains. Here, two CTX‐M‐15 positive cefotaxime resistant bacterial strains (i.e., one Escherichia coli and one Klebsiella pneumoniae strain) were used for testing the efficacy of “cefotaxime loaded gold‐nanoparticles.” Bromelain was used for both reduction and capping in the process of synthesis of gold‐nanoparticles. Thereafter, cefotaxime was conjugated onto it with the help of activator 1‐Ethyl‐3‐(3‐dimethylaminopropyl)‐carbodiimide. For characterization of both unconjugated and cefotaxime conjugated gold nanoparticles; UV‐Visible spectroscopy, Scanning, and Transmission type Electron Microscopy methods accompanied with Dynamic Light Scattering were used. We used agar diffusion method plus microbroth‐dilution method for the estimation of the antibacterial‐activity and determination of minimum inhibitory concentration or MIC values, respectively. MIC values of cefotaxime loaded gold nanoparticles against E. coli and K. pneumoniae were obtained as 1.009 and 2.018 mg/L, respectively. These bacterial strains were completely resistant to cefotaxime alone. These results reinforce the utility of conjugating an old unresponsive antibiotic with gold nanoparticles to restore its efficacy against otherwise resistant bacterial pathogens. J. Cell. Biochem. 118: 2802–2808, 2017.

Compounds isolated from Ageratum houstonianum inhibit the activity of matrix metalloproteinases (MMP-2 and MMP-9): An oncoinformatics study

Background: In osteosarcoma tissue, both MMP-2 and MMP-9 are over expressed compared to their expression in non-affected stromal tissue. Hence, gelatinases are attractive targets for anti-osteosarcoma drugs. Objective: To study the inhibitory activity of compounds isolated from Ageratum houstonianum against MMP-2 and MMP-9 by in-silico approach. Material and Methods: We performed docking study using ‘Autodock 4.2’ between 1,2-benzenedicarboxylic acid-bis (2-ethylhexyl) ester; squalene; 3,5-bis (1,1-dimethylethyl) phenol; pentamethyl tetrahydro-5H-chromene; (1, 4-cyclohexylphenyl) ethanone and 6-vinyl-7-methoxy-2,2-dimethylchromene with MMP-2 and MMP-9. Results: Among all six compounds isolated from Ageratum houstonianum, (1, 4-cyclohexylphenyl) ethanone showed the maximum potential as a putative inhibitor of both MMP-2 and MMP-9 enzymes with reference to ΔG (−7.95 and −8.2 kcal/mol, respectively) and Ki (1.48 and 0.98 μM, respectively) values. Total intermolecular energy of docking for (1, 4-cyclohexylphenyl) ethanone-MMP catalytic domain-interaction was found to be −8.55 kcal/mol for MMP-2 and −9.21 kcal/mol for MMP-9. Conclusion: This study explores molecular interactions between human MMPs (MMP-2 and MMP-9) and six natural compounds. This study predicts that (1,4-cyclohexylphenyl) ethanone is a more efficient inhibitor of human MMP-2 and MMP-9 enzymes compared to the other natural compounds used in this study with reference to Ki and ΔG values.

Prevalence of CTX-M resistance marker and integrons among Escherichia coli and Klebsiella pneumoniae isolates of clinical origin.

Bacterial pathogens producing CTX‐M beta‐lactamases are emerging around the world as a source of resistance to oxyimino cephalosporins such as cefotaxime. In this study, we have investigated the prevalence of blaCTX‐M genes among clinical isolates of Escherichia coli and Klebsiella pneumoniae. Of the double‐disk synergy test‐positive E. coli (n = 94) and Kl. pneumoniae (n = 73) strains isolated during the study period, 41 (44·08%) E. coli and 32 (43·24%) Kl. pneumoniae isolates were found to be positive for blaCTX‐M genes. Twenty‐two integrons (13 for E. coli and 9 for Kl. pneumoniae) were detected whose sizes ranged from 600 bp to 1·5 kb. All these integrons were found to be of Class1 type and were invariably PCR positive for int1 and sul1 genes. Marker transfer experiments demonstrated plasmid‐mediated transfer of cefotaxime and ceftazidime resistance markers. In addition, analysis of the enterobacterial repetitive intergenic consensus (ERIC)‐PCR typing of the blaCTX‐M‐carrying isolates showed that they were genetically diverse and heterogeneous suggesting that multiple subtypes of the species were involved in infection.

An enzoinformatics study for prediction of efficacies of three novel penem antibiotics against New Delhi metallo-β-lactamase-1 bacterial enzyme

New Delhi metallo-beta-lactamase (NDM-1) is a beta-lactamase (class B carbapenemase) containing Zn2+ and other divalent cations as cofactors which possesses the ability to inactivate all beta lactams (including carbapenems) except aztreonam by catalyzing the hydrolytic cleavage of the substrate amide bond. Carbapenemases are either serine enzymes or metallo-β-lactamases (MBLs) that utilize at least one zinc ion for hydrolysis. The present study describes the molecular interaction of carbapenems (Imipenem, Meropenem, Ertapenem, Doripenem, Panipenem, Biapenem, Razupenem, Faropenem, Tebipenem and Tomopenem) with NDM-1, β-lactamase enzyme. Docking between NDM-1 and each of these carbapenems (separately) was performed using ‘Autodock4.2’.

Preclinical Hepatoprotective Effect of Herbalism against Ethanol Induced Hepatotoxicity: A Review

BACKGROUND Liver ailments including alcoholic liver disease (ALD), still remain the main reason for morbidity & mortality worldwide. In fact, ALD is a multifactorial disease with complex pathophysiology which is linked to several types of liver damages including steatohepatitis, fibrosis and cirrhosis. METHODS This review emphasizes on 30 herbal medicinal plants with their extracts studied for protective effect against ALD and current scientific evidence of ALD cure by thirty Indian Materia Medica including Tilia Platyphyllos, Amomum subulatum, Carica papaya, Pogostemon patchouli, Commelina benghalensis, Bacopamonnieri, Pecan nut, Allium cepa, Beta Vulgaris, Adina cordifolia, Ocimum gratissimum, Vernonia amygdalina, Sida veronicaefolia, Chenopodium album, Korean red ginseng, Elephantopus scaber, Tecomella undulata, Prunus armeniaca, Sea tangle (Laminaria japonica), Emblica officinalis, Saccharum officinarum, Cocculus hirsutus, Cassia roxburghii, Zhi-Zi-Da- Huang, Phyllanthus amarus, Aegle marmelos, Agrimonia eupatoria, Flaveria trinervia, Curcuma longa and Garcinia indica. RESULTS Reduction in oxidative stress, improvement in inflammation, reduction in degeneration of fat and necrosis are some of the mechanisms of action of these medicinal plants observed in alcohol induced in-vivo and in-vitro liver injury models. CONCLUSION Accordingly, this review provides several evidences which show that these medicinal plants could be used for the treatment and prevention of ALD.

Comparative Inhibition Study of Compounds Identified in the Methanolic Extract of Apamarga Kshara Against Trichomonas vaginalis Carbamate Kinase (TvCK): An Enzoinformatics Approach.

Abstract In the present study, we have identified ten compounds, namely dodecanol acid, myristic acid, neophytadiene, palmitic acid, heptadecanoic acid, linoleic acid, elaidic acid, 3-7-dimethyl acid, stearic acid and methyl eicos acid, of the methanolic extract of Apamarga Kshara by GC–MS analysis. Apamarga Kshara has been reported to be active against cervical erosion. Major causal organism for cervical erosion is Trichomonas vaginalis. However, there is a paucity of information about the mechanism of action and inhibitory effect of the biologically active natural compounds presented in A. Kshara against this organism (T. vaginalis). Therefore, present investigation was conducted to observe possible interactions of these compounds on T. vaginalis carbamate kinase using molecular docking software ‘AutoDock 4.2.’ Identification of the amino acid residues crucial for the interaction between T. vaginalis carbamate kinase and these natural compounds is of due scientific interest. The study will aid in efficacious and safe clinical use of the above-mentioned compounds.

A neuroinformatics study to compare inhibition efficiency of three natural ligands (Fawcettimine, Cernuine and Lycodine) against Human Brain Acetylcholinesterase

Enzyme-inhibition is considered as a potent therapeutic approach to the treatment of diseases associated with acetylcholinesterase (AChE). The present study elucidates molecular interactions of human brain AChE, with three natural ligands Lycodine, Cernuine and Fawcettimine for comparison. Docking between these ligands and enzyme was performed using ‘Autodock 4.2’. It was determined that polar and hydrophobic interactions play an important role in the correct positioning of Lycodine, Cernuine and Fawcettimine within the ‘catalytic site’ of AChE to permit docking. This approach would be helpful to understand the selectivity of the given drug molecule in the treatment of neurological disorder. Moreover, the present study confirms that Lycodine is a more efficient inhibitor of human brain AChE compared to Cernuine and Fawcettimine with reference to ΔG and Ki values.