The small molecule nitazoxanide selectively disrupts BAM-mediated folding of the outer membrane usher protein
| Autor: | John J. Psonis, Peter Chahales, Paul S. Hoffman, Nadine S. Henderson, Nathan W. Rigel, David G. Thanassi |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Protein Folding Fimbria medicine.disease_cause Biochemistry Microbiology Pilus 03 medical and health sciences parasitic diseases medicine otorhinolaryngologic diseases Uropathogenic Escherichia coli Secretion Molecular Biology Escherichia coli 030102 biochemistry & molecular biology biology Antiparasitic Agents Chemistry Escherichia coli Proteins Cell Biology Periplasmic space Nitro Compounds Cell biology Thiazoles 030104 developmental biology Chaperone (protein) biology.protein Protein folding Bacterial outer membrane Bacterial Outer Membrane Proteins Molecular Chaperones |
| Zdroj: | J Biol Chem |
| ISSN: | 1083-351X |
| Popis: | Bacterial pathogens assemble adhesive surface structures termed pili or fimbriae to initiate and sustain infection of host tissues. Uropathogenic Escherichia coli, the primary causative agent of urinary tract infections, expresses type 1 and P pili required for colonization of the bladder and kidney, respectively. These pili are assembled by the conserved chaperone–usher (CU) pathway, in which a periplasmic chaperone works together with an outer membrane (OM) usher protein to build and secrete the pilus fiber. Previously, we found that the small molecule and antiparasitic drug nitazoxanide (NTZ) inhibits CU pathway–mediated pilus biogenesis in E. coli by specifically interfering with proper maturation of the usher protein in the OM. The usher is folded and inserted into the OM by the β-barrel assembly machine (BAM) complex, which in E. coli comprises five proteins, BamA–E. Here, we show that sensitivity of the usher to NTZ is modulated by BAM expression levels and requires the BamB and BamE lipoproteins. Furthermore, a genetic screen for NTZ-resistant bacterial mutants isolated a mutation in the essential BamD lipoprotein. These findings suggest that NTZ selectively interferes with an usher-specific arm of the BAM complex, revealing new details of the usher folding pathway and BAM complex function. Evaluation of a set of NTZ derivatives identified compounds with increased potency and disclosed that NTZ's nitrothiazole ring is critical for usher inhibition. In summary, our findings indicate highly specific effects of NTZ on the usher folding pathway and have uncovered NTZ analogs that specifically decrease usher levels in the OM. |
| Databáze: | OpenAIRE |
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