Characterisation of a Novel Producer, the Antimicrobial Properties and the Molecular Target of Zelkovamycin

Tarantini, Francesco Saverio (2020) Characterisation of a Novel Producer, the Antimicrobial Properties and the Molecular Target of Zelkovamycin. PhD thesis, University of Nottingham.

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The rise of antimicrobial resistance poses a threat to the treatment of infections caused by pathogenic and opportunistic bacteria, including Staphylococcus aureus and Pseudomonas aeruginosa.

In a time of relentless search for new antibiotics, the recent isolation of a novel producer of zelkovamycin offered the opportunity to investigate the unidentified biosynthetic gene cluster of the antibiotic and encouraged the elucidation of its antimicrobial properties and uncertain target.

In the first part of this work, the polyphasic characterisation the novel actinomycete strain 32-07 is presented. Based on its genome and 16S rRNA sequence, the microorganism was found to belong to the genus Actinomadura. Its phenotypic and genotypic characteristics, however, distinguished the isolate from its closest relative and its classification as Actinomadura graeca was therefore proposed. The new species was also confirmed as a producer of the antibiotic zelkovamycin, for which the putative biosynthetic cluster was identified.

The antimicrobial properties of zelkovamycin against P. aeruginosa PAO1-L and S. aureus SH1000 are elucidated in the second part of the study. The antibiotic was confirmed effective against S. aureus and its previously unreported activity against P. aeruginosa was uncovered and characterised. In both species, zelkovamycin appeared to easily permeate cell membranes, although a marked increase in its activity was recorded against an efflux-deficient P. aeruginosa mutant. It is therefore postulated that zelkovamycin may be subject to active efflux in Gram-negative bacteria.

The last part of this manuscript focuses on the investigation and identification of the molecular target of zelkovamycin. Each of several single amino acid substitutions in a single protein were found to confer S. aureus high resistance to the antibiotic, confirming the role of the protein as the target for zelkovamycin.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Chan, Weng
Williams, Paul
Heeb, Stephan
Keywords: antimicrobial resistance, zelkovamycin, peptide antibiotics
Subjects: Q Science > QR Microbiology > QR 75 Bacteria. Cyanobacteria
Q Science > QR Microbiology > QR100 Microbial ecology
R Medicine > RS Pharmacy and materia medica
Faculties/Schools: UK Campuses > Faculty of Science > School of Pharmacy
Item ID: 60112
Depositing User: TARANTINI, Francesco
Date Deposited: 12 Oct 2023 14:28
Last Modified: 13 Oct 2023 04:30

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