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Title: Characterisation of symmetric bis-benzimidazoles as antibacterial chemotherapeutic agents
Author: Carraco Moreira, Joao Bruno
Awarding Body: University of London
Current Institution: University of London
Date of Award: 2012
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Nosocomial and community-acquired infections due to methicillin-resistant Staphylococcus aureus (MRSA) and other Gram-positive bacteria are associated with high levels of mortality, morbidity and significant social and economic costs in the U.K. and elsewhere. As the evolution of multi-drug resistance relentlessly erodes the utility of currently available antibacterial drugs, it is essential to maintain efforts to search for new classes of antibacterial agents. Benzimidazoles are potent antihelmintic agents discovered in 1961. Chemical modifications led to the synthesis of the head-to-tail fluorochrome Hoechst 33258 and, more recently, to symmetric head-to-head bis-benzimidazoles (sBBZ). The antibacterial potential of these compounds was examined. Antibacterial activity was evaluated by minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) assays using a total of 143 Gram-positive isolates, including 61 MRSA, 12 vancomycin resistant enterococci (VRE), 12 Streptococcus pneumoniae, 11 Listeria monocytogenes, 7 Mycobacterium spp. (including Mycobacterium tuberculosis) and 14 Gram-negative isolates. Structure-activity relationships were determined and key requirements for activity were identified. Acute toxicity of sBBZs was assessed using the sulforhodamine B staining method and a zebrafish embryo model. To clarify mode of action, time kill studies, flow cytometry, DNA microarrays and radioisotope incorporation assays were employed. sBBZs displayed activity against Gram-positive but not Gram-negative pathogens; the most potent compound possessed MIC90 values of 0.06, 0.125 and 1 mg/L against, respectively, MRSA, VRE and M tuberculosis isolates. Data suggests that sBBZs are bacteriostatic agents that interfere primarily with the DNA machinery and do not select for drug resistant variants over a 31-day period of drug exposure. Subtle structural modifications have an incisive effect on in vitro potency of sBBZs. Toxicity was determined as minimal for WI-38 cell line and the zebrafish embryo model of infection. Sub-inhibitory concentrations of sBBZs inhibited MRSA transcription of pathogenicity-associated genes. Symmetric bis-benzimidazoles are new DNA-interfering bacteriostatic agents with potent antibacterial activity and significant therapeutic potential against Gram-positive bacteria, including MRSA and M tuberculosis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available