Mode of action of closthioamide: the first member of the polythioamide class of bacterial DNA gyrase inhibitors

摘要: OBJECTIVES The spread of MDR bacteria represents a serious threat to human society and novel antibiotic drugs, preferably from new chemical classes, are urgently needed. Closthioamide was isolated the strictly anaerobic bacterium Clostridium cellulolyticum belongs class natural products, polythioamides. Here, we investigated antimicrobial activity mechanism action closthioamide. METHODS For assessing closthioamide, MIC values killing kinetics were determined. To identify its target pathway, whole-cell-based assays used including analysis macromolecular synthesis recording susceptibility profile library clones with down-regulated potential genes. Subsequently, inhibitory effect closthioamide on enzymes, e.g. DNA gyrase topoisomerase IV, evaluated. RESULTS had broad-spectrum against Gram-positive bacteria. Notably, very potent MRSA VRE strains. impaired replication inhibited activity, in particular ATPase function whereas there little cleavage-rejoining function. also relaxation gyrase, which does not require ATP hydrolysis, thus may allosterically rather than directly interfere gyrase. Cross-resistance ciprofloxacin novobiocin could be detected experimental mutants clinical isolates. CONCLUSIONS Closthioamide, member an unprecedented antibiotics, is inhibitor bacterial gyrase; however, molecular differs that quinolones aminocoumarins.