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A conserved zinc-binding site in Acinetobacter baumannii PBP2 required for elongasome-directed bacterial cell shape
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Micelli, Carmina, Dai, Yunfei, Raustad, Nicole, Isberg, Ralph R., Dowson, Christopher G., Lloyd, Adrian J., Geisinger, Edward, Crow, Allister and Roper, David I. (2023) A conserved zinc-binding site in Acinetobacter baumannii PBP2 required for elongasome-directed bacterial cell shape. Proceedings of the National Academy of Sciences of the United States of America, 120 (8). e2215237120. doi:10.1073/pnas.2215237120 ISSN 0027-8424.
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WRAP-conserved-zinc-binding-site-Acinetobacter-baumannii-PBP2-required-elongasome-directed-bacterial-cell-shape-2023.pdf - Published Version - Requires a PDF viewer. Available under License Creative Commons Attribution 4.0. Download (3577Kb) | Preview |
Official URL: http://dx.doi.org/10.1073/pnas.2215237120
Abstract
Acinetobacter baumannii is a gram-negative bacterial pathogen that causes challenging nosocomial infections. β-lactam targeting of penicillin-binding protein (PBP)–mediated cell wall peptidoglycan (PG) formation is a well-established antimicrobial strategy. Exposure to carbapenems or zinc (Zn)-deprived growth conditions leads to a rod-to-sphere morphological transition in A. baumannii, an effect resembling that caused by deficiency in the RodA–PBP2 PG synthesis complex required for cell wall elongation. While it is recognized that carbapenems preferentially acylate PBP2 in A. baumannii and therefore block the transpeptidase function of the RodA–PBP2 system, the molecular details underpinning cell wall elongation inhibition upon Zn starvation remain undefined. Here, we report the X-ray crystal structure of A. baumannii PBP2, revealing an unexpected Zn coordination site in the transpeptidase domain required for protein stability. Mutations in the Zn-binding site of PBP2 cause a loss of bacterial rod shape and increase susceptibility to β-lactams, therefore providing a direct rationale for cell wall shape maintenance and Zn homeostasis in A. baumannii. Furthermore, the Zn-coordinating residues are conserved in various β- and γ-proteobacterial PBP2 orthologs, consistent with a widespread Zn-binding requirement for function that has been previously unknown. Due to the emergence of resistance to virtually all marketed antibiotic classes, alternative or complementary antimicrobial strategies need to be explored. These findings offer a perspective for dual inhibition of Zn-dependent PG synthases and metallo-β-lactamases by metal chelating agents, considered the most sought-after adjuvants to restore β-lactam potency against gram-negative bacteria.
| Item Type: | Journal Article | |||||||||||||||||||||||||||||||||
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| Subjects: | Q Science > QH Natural history Q Science > QP Physiology Q Science > QR Microbiology |
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| Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | |||||||||||||||||||||||||||||||||
| Library of Congress Subject Headings (LCSH): | Morphogenesis , Peptidoglycans , Penicillin resistance, Protein binding, Gram-negative bacteria, Drug resistance in microorganisms, Zinc -- Physiological effect, Homeostasis, Acinetobacter | |||||||||||||||||||||||||||||||||
| Journal or Publication Title: | Proceedings of the National Academy of Sciences of the United States of America | |||||||||||||||||||||||||||||||||
| Publisher: | National Academy of Sciences | |||||||||||||||||||||||||||||||||
| ISSN: | 0027-8424 | |||||||||||||||||||||||||||||||||
| Official Date: | 14 February 2023 | |||||||||||||||||||||||||||||||||
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| Volume: | 120 | |||||||||||||||||||||||||||||||||
| Number: | 8 | |||||||||||||||||||||||||||||||||
| Article Number: | e2215237120 | |||||||||||||||||||||||||||||||||
| DOI: | 10.1073/pnas.2215237120 | |||||||||||||||||||||||||||||||||
| Status: | Peer Reviewed | |||||||||||||||||||||||||||||||||
| Publication Status: | Published | |||||||||||||||||||||||||||||||||
| Access rights to Published version: | Open Access (Creative Commons) | |||||||||||||||||||||||||||||||||
| Date of first compliant deposit: | 15 February 2023 | |||||||||||||||||||||||||||||||||
| Date of first compliant Open Access: | 17 February 2023 | |||||||||||||||||||||||||||||||||
| RIOXX Funder/Project Grant: |
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