25 research outputs found
4-AMINOTHIAZOLYL ANALOGS OF GE2270 A: DESIGN, SYNTHESIS AND EVALUATION OF IMIDAZOLE ANALOGS
No full textImidazole analogs of the antibiotic natural product GE2270 A (1) were designed, synthesized, and evaluated for Gram positive bacteria growth inhibition. A recently reported, copper-mediated synthesis was exploited to prepare the 4-thiazolyl imidazole analogs of GE2270 A. The synthesis described represents a structurally complex, natural product-based application of this recently reported synthetic methodology. In addition, the biological evaluation of the imidazole-based analogs further define the SAR of the 4-aminothiazolyl-based template
4-Aminothiazolyl Analogs of GE2270 A: Antibacterial Lead Finding
No full text4-Aminothiazolyl analogs of the antibacterial natural product GE2270 A (1) were designed, synthesized, and evaluated for G+ bacteria growth inhibition. The aminothiazole-based chemical template was evaluated for chemical stability and its decomposition revealed a novel, structurally simplified, des-thiazole analog of GE2270 A. Subsequent stabilization of the 4-aminothiazolyl functional motif was achieved and initial structure activity relationships defined
Antibiotic Optimization and Chemical Structure Stabilization of Thiomuracin A
No full textSynthetic studies of the antimicrobial secondary metabolite thiomuracin A (1) were initiated in order to improve chemical stability and physicochemical properties. Functional group manipulation of thiomuracin A included: removal of the C2-C7 sidechain, derivatization of the C84 epoxide region, and removal of the C44 hydroxyphenylalanine motif. The resulting derivatives stabilized and simplified the chemical structure while retaining potent antibacterial activity as compared to thiomuracin A, and facilitated isolation and further material supply for continued medicinal chemistry optimization
Reduced susceptibility of Haemophilus influenzae to the peptide deformylase inhibitor LBM415 can result from target protein overexpression due to amplified chromosomal def gene copy number.
No full textPrevious genetic analysis of Haemophilus influenzae revealed two mechanisms associated with decreased susceptibility to the novel peptide deformylase inhibitor LBM415: AcrAB-TolC-mediated efflux and Fmt bypass, resulting from mutations in the pump repressor gene acrR and in the fmt gene, respectively. We have isolated an additional mutant, CDS23 (LBM415 MIC, 64 microg/ml versus 4 microg/ml against the parent strain NB65044) that lacks mutations in the acrR or fmt structural genes or in the gene encoding Def, the intracellular target of LBM415. Western immunoblot analysis, two-dimensional gel electrophoresis, and tryptic digestion combined with mass spectrometric identification showed that the Def protein was highly overexpressed in the mutant strain. Consistent with this, real-time reverse transcription-PCR revealed a significant increase in def transcript titer. No mutations were found in the region upstream of def that might account for altered expression; however, pulsed-field gel electrophoresis suggested that a genetic rearrangement of the region containing def had occurred. Using a combination of PCR, sequencing, and Southern blot analyses, it was determined that the def gene had undergone copy number amplification, explaining the high level of target protein expression. Inactivation of the AcrAB-TolC efflux pump in this mutant increased susceptibility 16-fold, highlighting the role of efflux in exacerbating the overall reduced susceptibility resulting from target overexpression
