NOVEL ANTIBIOTICS FOR VANCOMYCIN RESISTANT INFECTION

Project: Research project

Description

The long term goal of my laboratory program is to apply the "one- bead one-compound" combinatorial library method (that was originally developed in my laboratory) to basic research and drug discovery involving the areas of infectious disease and cancer. Development and spread of multi-resistant bacterial pathogens are becoming one of the major problems in clinical Medicine. From 1/1/89 to 3/31/93, 16,571 cases of enterococci noscomial infections in hospitals were reported to the National Noscomial Infection Surveillance system. It was alarming to notice that during this 4 year period, enterococcal isolates resistant to vancomycin, particularly from patients in intensive care units, rose from 0.3% to 13.0% and the rate continued to rise in 1994 and 1995. There is a definite need for the development of new antibiotics that are effective in the treatment of vancomycin-resistant infections. Vancomycin works by binding tightly to peptidoglycan strands in the bacterial cell wall terminates in D-Ala-D-Ala. This complexation blocks transglycosylation and transpeptidation of nascent peptidoglycan strands. As a result, the peptidoglycan structure is weakened rendering the bacteria susceptible to osmotic lysis. Vancomycin resistant cells have replaced the normal D-Ala- D-Ala peptidoglycan termini with D-Ala-D-Lactate termini that are no longer recognized by vancomycin. In this proposal we hypothesize that using D-Ala-D-Ala as a probe to screen "one-bead one-compound" combinatorial peptide libraries, we will be able to identify D-Ala-D-Ala binders that have antibacterial activity. We further hypothesize that an antibiotic that can overcome vancomycin resistance can be discovered by screening combinatorial libraries with a D-Alan-D-Lactate probe. Tow assay approaches will be used for the library screening: the enzyme-linked colorimetric assay and the radiometric assay. The positive leads will be resynthesized and their antibacterial activity as well as physico-chemical interaction with D-Ala-D-Lactate will be determined. The active leads will then be further optimized with various approaches. Peptide libraries with secondary or constrained structures will be used in this study.
StatusFinished
Effective start/end date8/1/977/31/00

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

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Vancomycin
Peptidoglycan
Anti-Bacterial Agents
Peptide Library
Infection
Lactic Acid
Vancomycin Resistance
Clinical Medicine
Enterococcus
Drug Discovery
Cross Infection
Cell Wall
Communicable Diseases
Intensive Care Units
Bacteria
alanylalanine
Enzymes
Research
Neoplasms

ASJC

  • Medicine(all)
  • Immunology and Microbiology(all)