Myxobacterium-produced antibiotic TA (myxovirescin) inhibits type II signal peptidase.
Antibiotic TA is a macrocyclic secondary metabolite produced by myxobacteria that has broad-spectrum bactericidal activity. The structure of TA is unique, and its molecular target is unknown. Here, we sought to elucidate TA's mode of action (MOA) through two parallel genetic approaches. First, chromosomal Escherichia coli TA-resistant mutants were isolated. One mutant that showed specific resistance toward TA was mapped and resulted from an IS4 insertion in the lpp gene, which encodes an abundant outer membrane (Braun's) lipoprotein. In a second approach, the comprehensive E. coli ASKA plasmid library was screened for overexpressing clones that conferred TA(r). This effort resulted in the isolation of the lspA gene, which encodes the type II signal peptidase that cleaves signal sequences from prolipoproteins. In whole cells, TA was shown to inhibit Lpp prolipoprotein processing, similar to the known LspA inhibitor globomycin. Based on genetic evidence and prior globomycin studies, a block in Lpp expression or prevention of Lpp covalent cell wall attachment confers TA(r) by alleviating a toxic buildup of mislocalized pro-Lpp. Taken together, these data argue that LspA is the molecular target of TA. Strikingly, the giant ta biosynthetic gene cluster encodes two lspA paralogs that we hypothesize play a role in producer strain resistance.
Department of Molecular Biology, University of Wyoming, Laramie, Wyoming, USA.
Yao
Y
Xiao
Klaus
K
Gerth
Rolf
R
Müller
Daniel
D
Wall
D000900:Anti-Bacterial Agents / Q000096:biosynthesis / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000235:genetics; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D002874:Chromosome Mapping; D002876:Chromosomes, Bacterial / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D024881:Drug Resistance, Bacterial / Q000235:genetics; D004926:Escherichia coli / Q000187:drug effects; D018942:Macrolides / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008856:Microscopy, Fluorescence; D016296:Mutagenesis; D016941:Myxococcus xanthus / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D010957:Plasmids / Q000235:genetics; D011480:Protease Inhibitors / Q000494:pharmacology*; D014176:Protein Biosynthesis / Q000187:drug effects
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D018942:Macrolides; D010455:Peptides; D011480:Protease Inhibitors; C035536:Myxococcus xanthus antibiotic TA; C017339:globomycin; D016282:Aspartic Acid Endopeptidases; C095652:signal peptidase II