Taxonomic group: bacteria / Proteobacteria
(Phylum: Proteobacteria)
Organ / tissue: capsule
NCBI PubMed ID: 39528188Publication DOI: 10.1016/j.ijbiomac.2024.137486Journal NLM ID: 7909578Publisher: Butterworth-Heinemann
Correspondence: sharon.leung
cuhk.edu.hk
Institutions: School of Pharmacy, the Chinese University of Hong Kong, Hong Kong, China, Emergency Medicine Clinical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China, Department of Chemistry, the Chinese University of Hong Kong, Hong Kong, China, Department of Pharmaceutics, UCL School of Pharmacy, University College London, London, UK, Sydney Pharmacy School, University of Sydney, Sydney, Australia
The emergence of multidrug-resistant Acinetobacter baumannii (MDR-AB), which most commonly manifests as pneumonia, has posed significant clinical challenges and called for novel treatment strategies. Phage depolymerases, which degrade bacterial surface carbohydrates, have emerged as potential antimicrobial agents. However, their preclinical application is limited to systemic infections due to their dependency on serum-mediated bacterial killing. To extend the treatment paradigm of depolymerase to low-serum lung infections, we explored the feasibility of applying phage depolymerase to potentiate antibiotic efficacy in controlling MDR-AB pneumonia. Using a model depolymerase, Dpo71, we observed that it could effectively potentiate antibiotic efficacy against MDR-AB2 bacteria in low-serum conditions mimicking lung milieu but showed no adjuvant effect in serum-free conditions. Unprecedentedly, we reported this low-serum-dependent mechanism that polysaccharide-degrading enzyme Dpo71 exposed bacteria to serum-induced membrane permeabilization and oxidative phosphorylation pathway inhibition, leading to a weakened ATP-dependent efflux pump and strengthened ROS-induced membrane permeabilization. These joint effects facilitated antibiotic (ceftazidime, CFZ) binding, ultimately exerting bactericidal effects. Resultantly, the bacterial load in the lungs of the Dpo71-CFZ combination group was significantly reduced compared with the Dpo71-alone and CFZ-alone groups. Overall, this study unravels the low-serum-dependent mechanisms by which depolymerase potentiated antibiotic efficacy, highlighting its potential as a novel strategy to enhance antibiotic activity against severe pneumonia
serum, Acinetobacter baumannii pneumonia, antibiotic potentiation, multidrug-resistance, phage-derived polysaccharide depolymerases, synergism
Structure type: polymer chemical repeating unit
Location inside paper: ref. 30
Compound class: CPS, polysaccharide
Contained glycoepitopes: IEDB_130648,IEDB_134627,IEDB_136044,IEDB_137472,IEDB_137473,IEDB_141794,IEDB_142488,IEDB_146664,IEDB_147450,IEDB_190606,IEDB_838988,IEDB_838989,IEDB_983931,SB_165,SB_166,SB_187,SB_192,SB_195,SB_21,SB_23,SB_24,SB_7,SB_8,SB_88
Methods: DNA sequencing, biological assays, extraction, dialysis, spectrophotometry, TEM, centrifugation, gene cloning, column chromatography, gene techniques, MIC assay, inhibition assay, binding assay
Related record ID(s): 30077
NCBI Taxonomy refs (TaxIDs): 470Reference(s) to other database(s): GTC:G97931NE, GenDB:JX976549.1
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There is only one chemically distinct structure:
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