Macrocycles as novel antibiotic adjuvants for the treatment of Pseudomonas aeruginosa infections

Langendonk, R Frèdi (2023) Macrocycles as novel antibiotic adjuvants for the treatment of Pseudomonas aeruginosa infections. PhD thesis, University of Liverpool.

Text 201219143_FEB2023.pdf - Unspecified Access to this file is embargoed until 1 August 2028. Download (49MB)

Abstract

Antimicrobial resistance of bacterial pathogens is a global health crisis. The development of novel antimicrobials has remained stagnant over the last decades due to lack of economic incentives, difficulty in developing such therapeutics, and concerns about resistance arising from selective pressure from bacteriostatic or bactericidal agents. An attractive solution, to mitigate the gap between the demand for novel antimicrobials and the diminishing supply pipeline, is the use of antibiotic adjuvants, which have the potential to extend the shelf-life of traditional antimicrobials. This study aimed to identify and characterize macrocycle molecules as novel antibiotic adjuvants for the WHO priority 1, and primary cystic fibrosis (CF) lung pathogen, Pseudomonas aeruginosa. From screening of a synthetic macrocycle compound library, several molecules were identified as antibiotic adjuvants, and four were shortlisted for further development. These four macrocycles functioned as adjuvants with two distinct classes of antibiotics and displayed activity against P. aeruginosa isolates from both chronic and acute infection. In addition, macrocycles displayed promising activity against common multidrug resistant nosocomial ESKAPE pathogens in vitro. Drug suitability and DMPK assessment in vitro and in silico revealed no major DMPK concerns, but several minor concerns were determined. One macrocycle was investigated in relevant physiological environments, and this macrocycle displayed promising activity in an ex vivo model of CF sputum, and an in vivo infection model of the wax moth larvae, Galleria mellonella. This lead compound was additionally tested in a murine P. aeruginosa sepsis model pilot study, but results were inconclusive. Exploration into target deconvolution and mechanism of action of the four macrocycles identified a putative P. aeruginosa protein target for one macrocycle. This was the DHDPS enzyme DapA, involved in the DAP-pathway for meso-DAP and lysine biosynthesis. This enzyme has previously been highlighted as a potential target for novel antimicrobials. In conclusion, this study identified four structurally unrelated macrocycles with favourable drug-like properties, and promising antibiotic adjuvant activity against P. aeruginosa, in vitro and in in vivo. Future priorities include extensively evaluating these macrocycles in relevant in vivo models for their efficacy and pharmacokinetics in mammalian systems.

Item Type:	Thesis (PhD)
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Infection, Veterinary and Ecological Sciences
Depositing User:	Symplectic Admin
Date Deposited:	24 Aug 2023 15:26
Last Modified:	24 Aug 2023 15:27
DOI:	10.17638/03171193
Supervisors:	Neill, Daniel Fothergill, Joanne
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3171193