Pre-clinical studies on novel lipid therapeutics with anti-virulence and antibiotic synergising potential against Pseudomonas aeruginosa isolates from bronchiectatic airways

  • James McSorley

Student thesis: Doctoral Thesis

Abstract

Chronic infections of the airways remain the leading cause of mortality in cystic fibrosis. Antibiotic therapy has drastically improved survival in this patient cohort, however, this therapy seldom, if ever, results in bacteriologic eradication of the infecting organism and acts only to suppress infection. The efficacy of such therapy may also be undermimed by the emergence of drug resistant strains, some of which may also display enhanced virulence and this is further confounded by the fact that antibiotic development has virtually drawn to a halt in recent decades.It is therefore imperative that potential alternatives to conventional antibiotics are sought to aid management of these infections. Use of phospholipid vesicles in these conditions may be one such alternative. Here, the potential of a multi-lamellar liposome based upon host lamellar bodies, LMS-611, to act as an anti-virulence agent and antibiotic synergist is explored in vitro with clinical isolates of the respiratory pathogen Pseudomonas aeruginosa. LMS-611 was found to reduce accumulation of elastase, pyocyanin, exopolysaccharide and the siderophores pyoverdine and pyochelin.LMS-611 does not reduce biofilm accumulation or viability in these models but microscopic evidence suggests that it modifies biofilm architecture, leading to the formation of homogenous layers rather than differentiated three dimensional structures. Studies are also conducted upon micelles composed of monopalmitoylphosphatidic acid (MPPA), a lysophospholipid which occurs naturally in inflammatory exudates and has previously been reported to have anti-microbial effects.It is discovered that MPPA reduces accumulation of pyocyanin by some strains and it is suggested on the basis of gene expression, growth kinetics and phenotype microarrays that this may be the result of enhanced growth and catabolite repression. Hitherto unknown interactions of MPPA with non β-lactam antibiotics are also uncovered and possible reasons suggested for these. Paradoxically, it is found that MPPA increases both biofilm accumulation and swimming motility.
Date of Award1 Oct 2015
LanguageEnglish
Awarding Institution
  • University Of Strathclyde
SponsorsScottish Funding Council SFC & University of Strathclyde
SupervisorNicholas Tucker (Supervisor) & (Supervisor)

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