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Biomedical subjects

I Chopra

Publications and source records attributed to I Chopra.

At least 37 records · Page 2Linked to original sources
PubMed1999

Expression of the Staphylococcus aureus UDP-N-acetylmuramoyl- L-alanyl-D-glutamate:L-lysine ligase in Escherichia coli and effects on peptidoglycan biosynthesis and cell growth.

The monomer units in the Escherichia coli and Staphylococcus aureus cell wall peptidoglycans differ in the nature of the third amino acid in the L-alanyl-gamma-D-glutamyl-X-D-alanyl-D-alanine side chain, where X is meso-diaminopimelic acid or L-lysine, respectively. The murE gene from S. aureus encoding the UDP-N-acetylmuramoyl-L-alanyl-D-glutamate: L-lysine ligase was identified and cloned into plasmid vectors. Induction of its overexpression in E. coli rapidly results in abnormal morphological changes and subsequent cell lysis. A reduction of 28% in the peptidoglycan content was observed in induced cells, and analysis of the peptidoglycan composition and structure showed that ca. 50% of the meso-diaminopimelic acid residues were replaced by L-lysine. Lysine was detected in both monomer and dimer fragments, but the acceptor units from the latter contained exclusively meso-diaminopimelic acid, suggesting that no transpeptidation could occur between the epsilon-amino group of L-lysine and the alpha-carboxyl group of D-alanine. The overall cross-linking of the macromolecule was only slightly decreased. Detection and analysis of meso-diaminopimelic acid- and L-lysine-containing peptidoglycan precursors confirmed the presence of L-lysine in precursors containing amino acids added after the reaction catalyzed by the MurE ligase and provided additional information about the specificity of the enzymes involved in these latter processes.

Bacteriolysis↗
PubMed1999

Prospects for antisense agents in the therapy of bacterial infections.

Antisense agents have received widespread interest as potential therapeutic agents for a number of diseases, including cancer, inflammatory conditions and viral infections. However, less emphasis has been placed on their potential application in the therapy of bacterial infections. This review considers the reported effects of backbone modified oligonucleotides (phosphorothioate and methyl phosphonate analogues) as well as peptide nucleic acids (PNAs) on gene expression and bacterial growth. In addition to suppressing bacterial growth by decreasing the expression of essential genes, it is also evident that antisense agents can be specifically targeted to genes that control expression of antibiotic resistance mechanisms, thereby potentially restoring an antibiotic-sensitive phenotype to the cell. Despite observations from several studies that antisense agents can interfere with bacterial gene expression in a sequence specific manner, their uptake into bacteria is poor. At present this is a limiting factor in their potential application as therapeutic agents for bacterial infections.

Journal Article↗
PubMed1999

Antimicrobial chemotherapy.

The antiviral, antibacterial and antifungal aspects of antimicrobial chemotherapy were all addressed during the International Congress of Chemotherapy. The growing problem of the emergence of antibiotic resistance in bacterial clinical isolates was particularly emphasized.

Journal Article↗
PubMed1999

New drugs for the chemotherapy of mycobacterial infections.

Infections caused by mycobacteria constitute important global health problems and during the last 50 years a number of drugs have achieved an established role in the therapy of these infections. However, the emergence of resistance to the current agents is creating a requirement for the development of new agents to address the challenges presented by drug-resistant mycobacteria. This article reviews the progress being made in the discovery and development of new drugs for the chemotherapy of mycobacterial infections. The topics include analogs of existing drugs, reassessment of older drug classes previously considered to have no role in mycobacterial chemotherapy and the prospects for oligonucleotide based therapies. The impact of genomics on drug discovery is also considered.

Journal Article↗
PubMed1998

Research and development of antibacterial agents.

Several new antibacterial agents are currently being developed in response to the emergence of bacterial resistance to existing drugs. The new agents include compounds that inhibit macromolecular synthesis or interfere with bacterial membrane function. Apart from the oxazolidinones and cationic peptides, the remainder of these new compounds are analogues of earlier antibiotic classes; therefore, it is probable that existing resistance mechanisms will adapt to accommodate the new derivatives. To minimise the potential for emergence of resistance to new agents, research strategies should be chosen that not only enhance the discovery of structurally novel drugs, but also direct these to new molecular targets that may themselves have decreased potential to give rise to drug-resistant variants.

Anti-Bacterial Agents↗
PubMed1998

Antibacterial spectra of drugs used for chemotherapy of mycobacterial infections.

The mechanism of action of many antimycobacterial agents is poorly understood. To obtain preliminary information on whether the targets for some of these drugs might also occur in other bacteria, the in vitro activities of selected agents against Escherichia coli, Bacillus subtilis and Staphylococcus aureus were determined. Dapsone, p-aminosalicylic acid and thiacetazone failed to inhibit the above organisms (MIC values > 100 micrograms/ml) that may therefore lack targets for these drugs. Capreomycin, viomycin and clofazimine demonstrated activity against some of the organisms (MIC values < 100 micrograms/ml) suggesting that the targets of these drugs may not be restricted to mycobacterial species. The agents were all potent inhibitors of Mycobacterium bovis bacille Calmette-Guérin (MIC values 0.08-0.5 microgram/ml).

Aminosalicylic Acid↗
PubMed1998

Joint tolerance to beta-lactam and fluoroquinolone antibiotics in Escherichia coli results from overexpression of hipA.

The basis of joint tolerance to beta-lactam and fluoroquinolone antibiotics in Escherichia coli mediated by hipA was examined. An antibiotic tolerance phenotype was produced by overexpression of hipA under conditions that did not affect the growth rate of the organism. Overexpressing hipA probably decreases the period in which bacteria are susceptible to the antibiotics by temporarily affecting some aspect of chromosome replication or cell division.

Anti-Bacterial Agents↗
PubMed1998

Chemotherapy of mycobacterial infections: molecular action of established drugs and investigational agents.

Infections caused by mycobacteria constitute important global health problems. During the last 50 years a number of drugs have achieved an established role in the therapy of these infections. These drugs, which are often used in combination, comprise both broad-spectrum agents that display antibacterial activity against mycobacteria and other organisms and narrow-spectrum agents whose activity is primarily restricted to mycobacteria, or even to individual mycobacterial species. In addition to the established agents, a number of investigational agents with antimycobacterial activity are at various stages in the research and development process. Several of the newer agents have arisen from the need to develop new drugs to combat the problems of emerging resistance to established agents. The mechanisms of action of the established drugs and investigational agents are reviewed in this update.

Journal Article↗
PubMed1998

Protein synthesis as a target for antibacterial drugs: current status and future opportunities.

The discovery and development of clinically useful antibiotic classes, such as the aminoglycosides, macrolides and tetracyclines, have clearly demonstrated that bacterial protein synthesis is a suitable target for drug intervention. New information on the binding of classical protein synthesis inhibitors to ribosomal RNA provides a rational explanation for their selective action against bacteria and also explains why chromosomal point mutations conferring resistance by structural changes at the target site are relatively rare in the majority of bacteria. These principles will be helpful when considering strategies for the screening or design of novel protein synthesis inhibitors that could be developed as new antibiotics. Recent progress in the discovery and development of bacterial protein synthesis inhibitors is illustrated by consideration of the glycylcyclines, ketolides, oxazolidinones and streptogramins.

Journal Article↗
PubMed1997

Molecular action of anti-mycobacterial agents.

In terms of the paradigms for antibacterial action presented in the introduction, there is good evidence that broad spectrum agents exert their anti-mycobacterial activity by interaction with classical targets occurring in a wide range of organisms including the mycobacteria. This is supported either by direct evidence (e.g., inhibition by rifampicin of mycobacterial RNA polymerase), or indirectly by the characterization of drug-resistant mycobacteria where mutations conferring resistance have been mapped to target sites homologous to those found in other bacteria (fluoroquinolones, macrolides, rifampicin, streptomycin). On the other hand, although the mode of action of some of the agents with an anti-mycobacterial spectrum is not fully understood, it is evident that the restricted spectrum is likely to arise from the possession of unique targets, or specific pro-drug conversion systems, or to a combination of both mechanisms. In several cases the narrow spectrum of the agents can be attributed to inhibition of molecular targets involved in the biosynthesis of the mycobacterial cell envelope that contains many unique polymers. The recent re-emergence of tuberculosis as an important human pathogen has led to improved methods for exploring the structure, biochemistry and genetics of the mycobacteria. These technical advances can now be used to gain a better understanding of the molecular basis of drug action in mycobacteria.

Antibiotics, Antitubercular↗
PubMed1997

Triiodothyronine (T3) reflects renal graft function after renal transplantation.

OBJECTIVE: Abnormalities in thyroid function are observed in patients with end stage renal disease. However, there are no data available evaluating sequential changes of thyroid function after renal transplantation. Therefore, we have studied thyroid hormone function in the immediate post-operative period after renal transplantation in order to determine the relationship between improving renal function and changes in thyroid hormone economy. DESIGN AND PATIENTS: Thyroid function was evaluated in 22 patients before and on days 1, 3, 7 and 15 after renal transplantation. All patients received prednisone and cyclosporin as immunosuppressive therapy. Twelve patients with normal renal function undergoing comparable surgical procedures served as a control group. MEASUREMENTS: Serum creatinine and thyroid hormone parameters (total T4, total T3, free T4, free T3, thyroxin binding globulin (TBG), reverse T3, T3 sulphate and TSH) were measured. RESULTS: According to post-operative kidney function after renal transplantation, patients could be subdivided into three groups: five patients had primary graft function (group I); seven patients had delayed graft function because of acute renal failure (group II); 10 patients had delayed graft function requiring high doses of prednisone and some also of OKT3 because of acute rejection (group III). There was a significant fall in T3 and T4 concentrations with a concomitant rise in reverse T3 in all patients up to 3 days after renal transplantation. However, only patients in group I reached pre-operative values on day 15 after renal transplantation (serum creatinine 167 +/- 52 microM), whereas patients in group II (creatinine 609 +/- 118 microM) and group III (creatinine 839 +/- 71 microM) continued to have T3 concentrations well in the hypothyroid range (group I, 1.68 +/- 0.28 nM) vs 0.87 +/- 0.09 nM in group II and 0.76 +/- 0.10 nM in group III; P < 0.01). Serum T4 concentrations were also low in group III (47.7 nM vs 100.2 nM in group I; P < 0.05) 15 days after renal transplantation. These changes were accompanied by a concomitant fall in T3/TBG ratio and in free T3. Elevated reverse T3 returned to normal values in all groups on the 15th day after renal transplantation. TSH fell significantly on the first post-operative day, but did not return to pre-operative values in renal transplantation patients. In the control group, TSH did not change during the study period. T3 sulphate, known to be elevated in chronic renal failure, remained above normal in all patients irrespective of graft function during this study period. CONCLUSIONS: T3 concentrations reflect renal graft function after renal transplantation. T3 is below normal in patients with delayed graft function (acute renal failure or acute rejection). The post-operative period (up to 3 days after renal transplantation) is associated with a low T3 syndrome. TSH does not return to pre-operative values even in patients with primary graft function. This might be due to the administration of prednisone. T3-sulphate is elevated before and after renal transplantation irrespective of graft function.

Acute Kidney Injury↗
PubMed1997

N-alkyl-substituted glycopeptide antibiotics.

The glycopeptide antibiotic vancomycin has proved valuable in the treatment of staphylococcal and enterococcal infections, particularly those caused by strains resistant to other antibiotics. The emergence of high-level resistance to vancomycin within the enterococci, and its potential for transfer to other pathogenic Gram-positive cocci, has led to interest in developing new glycopeptide antibiotics with activity against vancomycin resistant organisms. The N-alkylated glycopeptide antibiotics, under development by Lilly Research Laboratories, represent a new series of compounds possessing these properties. The lead compound in this series, LY 333328, is reported to be in Phase I trials.

Journal Article↗
PubMed1997

Approaches to antibacterial drug discovery.

The discovery of new antibacterial drugs can be based either upon empirical screening methods or structure-based design. Empirical methods utilise both intact bacteria and isolated biochemical targets for high throughput screening of natural product or chemical libraries to detect inhibitor leads. Structure-based methods for drug design are based upon understanding the molecular architecture of the active site in an appropriate target molecule. Empirical methods have been widely applied to screen for antibacterial agents and the introduction of combinatorial methods for the synthesis of chemical libraries considerably expands the potential of empirical screening methods. In contrast, structure-based drug design has not yet been widely applied to the development of antibacterial drugs, although it has proved to be a successful approach in other therapeutic areas. Recent advances in the sequencing of bacterial genomes will assist both empirical and structure-based approaches by identifying new, essential bacterial genes whose products may become the targets of new agents with selective antibacterial activity.

Journal Article↗
PubMed1995

SB 205952, a novel semisynthetic monic acid analog with at least two modes of action.

The biological properties of SB 205952, a nitrofuryl oxazole derivative of monic acid, differ from those of the closely related antibacterial agent mupirocin. Compared with mupirocin, SB 205952 has increased antimicrobial potency, an extended spectrum including mupirocin-resistant staphylococci, and rapid bactericidal activity. SB 205952, like mupirocin, is a potent inhibitor of bacterial isoleucyl-tRNA synthetase (IRS) in mupirocin-susceptible organisms but does not inhibit IRS from mupirocin-resistant staphylococci, indicating that SB 205952 has more than one mechanism of action. SB 205952 rapidly inhibits protein, RNA, and DNA syntheses in mupirocin-susceptible and mupirocin-resistant staphylococci. In each case, the effect on RNA synthesis is relaxed by treatment with chloramphenicol, indicating that inhibition of RNA synthesis is probably a secondary consequence of stringent control. It is proposed that SB 205952 possesses one or more mechanisms of action in addition to IRS inhibition, probably mediated by its nitrofuryl component.

Anti-Bacterial Agents↗
PubMed1994

Cytokines modulate type I iodothyronine deiodinase mRNA levels and enzyme activity in FRTL-5 rat thyroid cells.

Tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interferon-gamma (INF-gamma) have inhibitory effects on thyroid function both in vivo and in vitro. We have studied the effects of these cytokines on type I 5'-deiodinase (5'-DI) mRNA expression and enzyme activity in FRTL-5 cells maintained in standard cell culture medium containing 0 (5H) or 2 mIU/ml bovine TSH (6H). Northern blots were hybridized with 5'-DI cDNA. 5'-DI mRNA levels were reduced to 20% of control values after treating cells with 100 ng/ml TNF-alpha in 6H for 2 days while the corresponding enzyme activity was reduced 50%. Other cytokines, including IL-1beta and interferon-gamma, also significantly inhibited expression of 5'-DI in FRTL-5 cells grown in 6H medium. Because the majority of circulating T3 in the rat is secreted by the thyroid gland, the highly significant decline in the serum T3/T4 ratio following in vivo administration of cytokines may be due to their direct inhibitory effect on thyroidal 5'-DI expression.

Animals↗