Challenges and opportunities in the development of novel antimicrobial therapeutics for cystic fibrosis.

Barton, Thomas E ORCID: 0000-0002-4592-4261, Frost, Frederick ORCID: 0000-0002-3902-6502, Fothergill, Joanne L ORCID: 0000-0002-7012-1508 and Neill, Daniel R (2022) Challenges and opportunities in the development of novel antimicrobial therapeutics for cystic fibrosis. Journal of medical microbiology, 71 (12).

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Official URL: http://dx.doi.org/10.1099/jmm.0.001643

Abstract

Chronic respiratory infection is the primary driver of mortality in individuals with cystic fibrosis (CF). Existing drug screening models utilised in preclinical antimicrobial development are unable to mimic the complex CF respiratory environment. Consequently, antimicrobials showing promising activity in preclinical models often fail to translate through to clinical efficacy in people with CF. Model systems used in CF anti-infective drug discovery and development range from antimicrobial susceptibility testing in nutrient broth, through to 2D and 3D <i>in vitro</i> tissue culture systems and <i>in vivo</i> models. No single model fully recapitulates every key aspect of the CF lung. To improve the outcomes of people with CF (PwCF) it is necessary to develop a set of preclinical models that collectively recapitulate the CF respiratory environment to a high degree of accuracy. Models must be validated for their ability to mimic aspects of the CF lung and associated lung infection, through evaluation of biomarkers that can also be assessed following treatment in the clinic. This will give preclinical models greater predictive power for identification of antimicrobials with clinical efficacy. The landscape of CF is changing, with the advent of modulator therapies that correct the function of the CFTR protein, while antivirulence drugs and phage therapy are emerging alternative treatments to chronic infection. This review discusses the challenges faced in current antimicrobial development pipelines, including the advantages and disadvantages of current preclinical models and the impact of emerging treatments.

Item Type:	Article
Uncontrolled Keywords:	Humans, Pseudomonas aeruginosa, Pseudomonas Infections, Cystic Fibrosis, Cystic Fibrosis Transmembrane Conductance Regulator, Anti-Infective Agents, Anti-Bacterial Agents, Models, Biological, Persistent Infection
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:	06 Jan 2023 12:41
Last Modified:	17 Feb 2023 04:22
DOI:	10.1099/jmm.0.001643
Open Access URL:	https://www.microbiologyresearch.org/content/journ...
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3166819