TonB-dependent receptor repertoire of Pseudomonas aeruginosa for uptake of siderophore-drug conjugates
| Autor: | Lena Mazza, Lucile Moynié, Alexandre Luscher, Dirk Bumann, Thilo Köhler, James H. Naismith, Pamela Saint Auguste, Daniel Pletzer |
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| Přispěvatelé: | European Commission, University of St Andrews. School of Chemistry, University of St Andrews. EaSTCHEM |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Thiazoles/metabolism
0301 basic medicine Siderophore Cell Membrane Permeability Siderophores/metabolism Siderophores siderophore-drug conjugate medicine.disease_cause Bacterial Outer Membrane Proteins/genetics/metabolism Pharmacology (medical) Receptor Pseudomonas aeruginosa/genetics/metabolism ddc:616 biology Chemistry Anti-Bacterial Agents/metabolism QR Microbiology Monobactams/metabolism Membrane Proteins/genetics/metabolism 3. Good health Acinetobacter baumannii Anti-Bacterial Agents Infectious Diseases Carrier Proteins/genetics/metabolism Pseudomonas aeruginosa Bacterial Proteins/genetics/metabolism Bacterial outer membrane Cephalosporins/metabolism Bacterial Outer Membrane Proteins Monobactams RM Cell Membrane Permeability/drug effects In silico 030106 microbiology beta-Lactams Microbiology 03 medical and health sciences SDG 3 - Good Health and Well-being Beta-Lactams/metabolism Bacterial Proteins medicine TonB-dependent receptor Gene Mechanisms of Action: Physiological Effects Siderophore-drug conjugate Pharmacology Biological Transport/drug effects Membrane Proteins DAS Biological Transport biology.organism_classification RM Therapeutics. Pharmacology QR Cephalosporins Thiazoles Carrier Proteins Bacteria |
| Zdroj: | 'Antimicrobial Agents and Chemotherapy ', vol: 62, pages: e00097-18-1-e00097-18-11 (2018) Antimicrobial Agents and Chemotherapy Antimicrobial Agents and Chemotherapy, Vol. 62, No 6 (2018) pp. e00097-18 |
| ISSN: | 0066-4804 |
| Popis: | The conjugation of siderophores to antimicrobial molecules is an attractive strategy to overcome the low outer membrane permeability of Gram-negative bacteria. In this Trojan horse approach, the transport of drug conjugates is redirected via TonB-dependent receptors (TBDR), which are involved in the uptake of essential nutrients, including iron. Previous reports have demonstrated the involvement of the TBDRs PiuA and PirA from Pseudomonas aeruginosa and their orthologues in Acinetobacter baumannii in the uptake of siderophore-beta-lactam drug conjugates. By in silico screening, we further identified a PiuA orthologue, termed PiuD, present in clinical isolates, including strain LESB58. The piuD gene in LESB58 is located at the same genetic locus as piuA in strain PAO1. PiuD has a similar crystal structure as PiuA and is involved in the transport of the siderophore-drug conjugates BAL30072, MC-1, and cefiderocol in strain LESB58. To screen for additional siderophore-drug uptake systems, we overexpressed 28 of the 34 TBDRs of strain PAO1 and identified PfuA, OptE, OptJ, and the pyochelin receptor FptA as novel TBDRs conferring increased susceptibility to siderophore-drug conjugates. The existence of a TBDR repertoire in P. aeruginosa able to transport siderophore-drug molecules potentially decreases the likelihood of resistance emergence during therapy. |
| Databáze: | OpenAIRE |
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