Structural and Functional Basis for Targeting Campylobacter jejuni Agmatine Deiminase To Overcome Antibiotic Resistance
Campylobacter jejuni is the most common bacterial cause of gastroenteritis and a major contributor to infant mortality in the developing world. The increasing incidence of antibiotic-resistant C. jejuni only adds to the urgency to develop effective therapies. Because of the essential role that polyamines play, particularly in protection from oxidative stress, enzymes involved in the biosynthesis of these metabolites are emerging as promising antibiotic targets. The recent description of an alternative pathway for polyamine synthesis, distinct from that in human cells, in C. jejuni suggests this pathway could be a target for novel therapies. To that end, we determined X-ray crystal structures of C. jejuni agmatine deiminase (CjADI) and demonstrated that loss of CjADI function contributes to antibiotic sensitivity, likely because of polyamine starvation. The structures provide details of key molecular features of the active site of this protein. Comparison of the unliganded structure (2.1 Å resolution) to that of the CjADI–agmatine complex (2.5 Å) reveals significant structural rearrangements that occur upon substrate binding. The shift of two helical regions of the protein and a large conformational change in a loop near the active site generate a narrow binding pocket around the bound substrate. This change optimally positions the substrate for catalysis. In addition, kinetic analysis of this enzyme demonstrates that CjADI is an iminohydrolase that effectively deiminates agmatine. Furthermore, our data suggest that C. jejuni agmatine deiminase is a potentially important target for combatting antibiotic resistance, and these results provide a valuable framework for guiding future drug development.
- Research Organization:
- Argonne National Lab. (ANL), Argonne, IL (United States)
- Sponsoring Organization:
- USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division; National Inst. of General Medical Sciences; National Inst. of Health; NIH-ORIP HEI; National Science Foundation (NSF)
- Grant/Contract Number:
- AC02-06CH11357; P41 GM103403; S10 RR029205; DMR-0936384; GM-103485
- OSTI ID:
- 1430342
- Journal Information:
- Biochemistry, Vol. 56, Issue 51; ISSN 0006-2960
- Publisher:
- American Chemical Society (ACS)Copyright Statement
- Country of Publication:
- United States
- Language:
- ENGLISH
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