Showing papers by "Ian Chopra published in 1997"

The search for antimicrobial agents effective against bacteria resistant to multiple antibiotics.

Abstract: The discovery, development, and clinical use of antibiotics during the 20th century have decreased substantially the morbidity and mortality from bacterial infections. The antibiotic era began with the therapeutic application of sulfonamide drugs in the 1930s, followed by a “golden” period of discovery from approximately 1945 to 1970, when a number of structurally diverse, highly effective agents were discovered and developed (16). However, since the 1980s the introduction of new agents for clinical use has declined, reflecting both the challenge of identifying new drug classes and a declining commitment to antibacterial drug discovery by the pharmaceutical industry (11, 42, 53, 63). The same period with a reduced rate of introduction of new agents has been accompanied by an alarming increase in bacterial resistance to existing agents, resulting in the emergence of a serious threat to global public health (7, 9, 28, 39, 49, 60, 63, 64). The resistance problem demands that a renewed effort be made to seek antibacterial agents effective against pathogenic bacteria resistant to current antibiotics. This minireview reviews the status of research in this critical therapeutic area. We reevaluate the potential of older, unexploited agents and review current approaches to the discovery of new agents, including the identification of new molecular targets for antibiotic action. Although other approaches such as the use of vaccines, monoclonal antibodies, hematopoiesis-stimulating factors, and various immunoregulatory cytokines may prove to have utility against infections caused by antibiotic-resistant bacteria (7), this minireview is limited to discussion of antibacterial agents and strategies for the detection of new molecular targets.

Approaches to antibacterial drug discovery.

Abstract: 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.

N-alkyl-substituted glycopeptide antibiotics

Abstract: 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.