The phenoxy alkyl benzimidazoles
(PABs) have good antitubercular activity. We expanded our structure–activity
relationship studies to determine the core components of PABs required
for activity. The most potent compounds had minimum inhibitory concentrations
against Mycobacterium tuberculosis in the low nanomolar
range with very little cytotoxicity against eukaryotic cells as well
as activity against intracellular bacteria. We isolated resistant
mutants against PAB compounds, which had mutations in either Rv1339,
of unknown function, or qcrB, a component of the
cytochrome bc1 oxidase of the electron
transport chain. QcrB mutant strains were resistant to all PAB compounds,
whereas Rv1339 mutant strains were only resistant to a subset, suggesting
that QcrB is the target. The discovery of the target for PAB compounds
will allow for the improved design of novel compounds to target intracellular M. tuberculosis.
This study represents a systematic chemical and biological study of the rufomycin (RUF) class of cyclic heptapeptides, which our anti-TB drug discovery efforts have identified as potentially promising anti-TB agents that newly target the caseinolytic protein C1, ClpC1. Eight new RUF analogues, rufomycins NBZ1−NBZ8 (1−8), as well as five known peptides (9−13) were isolated and characterized from the Streptomyces atratus strain MJM3502. Advanced Marfey's and X-ray crystallographic analysis led to the assignment of the absolute configuration of the RUFs. Several isolates exhibited potent activity against both pathogens M. tuberculosis H37Rv and M. abscessus, paired with favorable selectivity (selectivity index >60), which collectively underscores the promise of the rufomycins as potential anti-TB drug leads.
Both natural and synthetic brominated furanones are known to inhibit biofilm formation by bacteria, but their toxicity to mammalian cells is often not reported. Here, we designed and synthesized a new class of brominated furanones (BBFs) that contained a bicyclic structure having one bromide group with well-defined regiochemistry. This class of molecules exhibited reduction in the toxicity to mammalian cells (human neuroblastoma SK-N-SH) and did not inhibit bacteria (Pseudomonas aeruginosa and Escherichia coli) growth, but retained the inhibitory activity towards biofilm formation of bacteria. In addition, all the BBFs inhibited the production of virulence factor elastase B in P. aeruginosa. To explore the effect of BBFs on quorum sensing, we used a reporter gene assay and found that 6-BBF and 7-BBF exhibited antagonistic activities for LasR protein in the lasI quorum sensing circuit, while 5-BBF showed agonistic activity for the rhlI quorum sensing circuit. This study suggests that structural variation of brominated furanones can be designed for targeted functions to control biofilm formation.
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