Dimers of nostocarboline with potent antibacterial activity.

Abstract:

OBJECTIVES:In this study, the in vitro antimicrobial activity and spectrum of new dimeric compounds derived from the cyanobacterial alkaloid nostocarboline were investigated. The mechanism of action and selectivity to bacteria were studied and compared to the cationic antiseptic chlorhexidine. METHODS:Minimal inhibitory concentrations were determined against clinical isolates and against a panel of microbial reference strains using the CLSI microdilution method. Bacterial membrane damage was addressed by measuring ATP leakage and the mode of action was investigated in Escherichia coli reporter strains. Selectivity was tested by a cytotoxicity assay using MTS. RESULTS:The antimicrobial potency of dimers varied with length of the hydrophobic linker. The most potent compounds, NCD9 and NCD10, had a C10 and C12 linker, respectively, and showed strong activity against Gram-positive bacteria, notably methicillin-resistant Staphylococcus aureus strains. Similar to chlorhexidine, these compounds showed a rapid concentration-dependent bactericidal effect, which correlated with membrane damage as indicated by ATP leakage. NCD9, in contrast to NCD10 and chlorhexidine, lacked activity against yeast strains and showed low cytotoxicity in CHO cells indicating a high degree of selectivity. In E. coli reporter strains, NCD9 induced the DegP response pathway as well as the SOS response, suggesting interaction with both the cell envelope and DNA metabolism. CONCLUSIONS:The results presented in this report indicate the potential of this new class of cationic antimicrobial compounds for the design of potent and selective antibacterials with low cytotoxicity.

journal_name

Chemotherapy

journal_title

Chemotherapy

authors

Locher HH,Ritz D,Pfaff P,Gaertner M,Knezevic A,Sabato D,Schroeder S,Barbaras D,Gademann K

doi

10.1159/000320033

subject

Has Abstract

pub_date

2010-01-01 00:00:00

pages

318-24

issue

4

eissn

0009-3157

issn

1421-9794

pii

000320033

journal_volume

56

pub_type

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