A conserved zinc-binding site in Acinetobacter baumannii PBP2 required for elongasome-directed bacterial cell shape

Author:

Micelli Carmina1,Dai Yunfei2ORCID,Raustad Nicole2,Isberg Ralph R.3,Dowson Christopher G.1ORCID,Lloyd Adrian J.1ORCID,Geisinger Edward2,Crow Allister1ORCID,Roper David I.1ORCID

Affiliation:

1. School of Life Sciences, University of Warwick, Coventry CV4 7AL, United Kingdom

2. Department of Biology, Northeastern University, Boston, MA 02115

3. Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA 02111

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.

Funder

UKRI | Biotechnology and Biological Sciences Research Council

UKRI | Medical Research Council

HHS | NIH | NIAID | Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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