Title | Non-coding nucleotides and amino acids near the active site regulate peptide deformylase expression and inhibitor susceptibility in Chlamydia trachomatis. |
Publication Type | Journal Article |
Year of Publication | 2011 |
Authors | Bao X, Pachikara ND, Oey CB, Balakrishnan A, Westblade LF, Tan M, Chase T, Nickels BE, Fan H |
Journal | Microbiology (Reading) |
Volume | 157 |
Issue | Pt 9 |
Pagination | 2569-2581 |
Date Published | 2011 Sep |
ISSN | 1465-2080 |
Keywords | 5' Flanking Region, Amidohydrolases, Amino Acid Substitution, Base Sequence, Catalytic Domain, Chlamydia trachomatis, Dipeptides, Drug Resistance, Bacterial, Enzyme Inhibitors, Enzyme Stability, Gene Expression Regulation, Bacterial, HeLa Cells, Humans, Kinetics, Mutation, Promoter Regions, Genetic, Transcription, Genetic |
Abstract | Chlamydia trachomatis, an obligate intracellular bacterium, is a highly prevalent human pathogen. Hydroxamic-acid-based matrix metalloprotease inhibitors can effectively inhibit the pathogen both in vitro and in vivo, and have exhibited therapeutic potential. Here, we provide genome sequencing data indicating that peptide deformylase (PDF) is the sole target of the inhibitors in this organism. We further report molecular mechanisms that control chlamydial PDF (cPDF) expression and inhibition efficiency. In particular, we identify the σ⁶⁶-dependent promoter that controls cPDF gene expression and demonstrate that point mutations in this promoter lead to resistance by increasing cPDF transcription. Furthermore, we show that substitution of two amino acids near the active site of the enzyme alters enzyme kinetics and protein stability. |
DOI | 10.1099/mic.0.049668-0 |
Alternate Journal | Microbiology (Reading) |
PubMed ID | 21719536 |
Grant List | AI071954 / AI / NIAID NIH HHS / United States |
Related Faculty:
Lars Westblade, Ph.D.