Journal article
Lethal synergy involving bicyclomycin: an approach for reviving old antibiotics
Journal of antimicrobial chemotherapy, Vol.69(12), pp.3227-3235
12/2014
DOI: 10.1093/jac/dku285
PMCID: PMC4228776
PMID: 25085655
Abstract
One way to address the growing problem of antimicrobial resistance is to revive old compounds that may have intrinsic lethal activity that is obscured by protective factors. Bicyclomycin is an old inhibitor of the Rho transcription terminator that by itself shows little rapid lethal activity. However, bicyclomycin participates in bacteriostatic synergy, which raises the possibility that conditions for lethal synergy may exist, perhaps through a suppression of protective factors.
Bicyclomycin was combined with bacteriostatic inhibitors of gene expression, and bactericidal activity was measured with several cultured Gram-negative pathogens.
When used alone, bicyclomycin failed to rapidly kill growing cultures of Escherichia coli; however, the additional presence of bacteriostatic concentrations of tetracycline, chloramphenicol or rifampicin led to rapid killing. Four other pathogen species, Acinetobacter baumannii, Klebsiella pneumoniae, Salmonella enterica serotype Typhimurium and Shigella dysenteriae, also exhibited enhanced killing when bicyclomycin was combined with tetracycline or rifampicin. This lethal synergy was achieved at low concentrations (slightly above the MIC) for all agents tested in combinations. Follow-up work with E. coli indicated that lethal synergy arose from a blockage of transcription elongation. Moreover, lethal synergy was reduced when bicyclomycin was added 60 min before tetracycline, suggesting that bicyclomycin induces a protective factor.
The action of bicyclomycin illustrates the potential present in a largely abandoned antibacterial agent; it exhibits lethal synergy when coadministered with known, bacteriostatic inhibitors of gene expression. The identification of protective factors, which are currently uncharacterized, may reveal new ways to promote the lethal action of some old antibiotics.
Details
- Title: Subtitle
- Lethal synergy involving bicyclomycin: an approach for reviving old antibiotics
- Creators
- Muhammad Malik - Rutgers, The State University of New JerseyLiping Li - Rutgers Biomedical and Health SciencesXilin Zhao - Rutgers, The State University of New JerseyRobert J Kerns - University of IowaJames M Berger - QB3Karl Drlica - Rutgers, The State University of New Jersey
- Resource Type
- Journal article
- Publication Details
- Journal of antimicrobial chemotherapy, Vol.69(12), pp.3227-3235
- DOI
- 10.1093/jac/dku285
- PMID
- 25085655
- PMCID
- PMC4228776
- ISSN
- 0305-7453
- eISSN
- 1460-2091
- Grant note
- 1DP2OD007423-01 / NIH HHS R01 AI087671 / NIAID NIH HHS DP2 OD007423 / NIH HHS AI087671 / NIAID NIH HHS R21 AI103781 / NIAID NIH HHS AI103781-01 / NIAID NIH HHS AI073491-06 / NIAID NIH HHS R01 AI073491 / NIAID NIH HHS
- Language
- English
- Date published
- 12/2014
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984366035302771
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