In Vivo Validation of Peptidoglycan Recycling as a Target to Disable AmpC-Mediated Resistance and Reduce Virulence Enhancing the Cell-Wall–Targeting Immunity

Author:

Torrens Gabriel1,Sánchez-Diener Irina1,Jordana-Lluch Elena1,Barceló Isabel María1,Zamorano Laura1,Juan Carlos1,Oliver Antonio1ORCID

Affiliation:

1. Servicio de Microbiología and Unidad de Investigación, Hospital Son Espases, Instituto de Investigación Sanitaria de Baleares, Palma, Spain

Abstract

Abstract Background Searching for new strategies to defeat Pseudomonas aeruginosa is of paramount importance. Previous works in vitro showed that peptidoglycan recycling blockade disables AmpC-dependent resistance and enhances susceptibility against cell-wall–targeting immunity. Our objective was to validate these findings in murine models. This study shows for the first time in different murine models of infection that blocking the peptidoglycan recycling in Pseudomonas aeruginosa causes an important virulence impairment and disables AmpC-mediated resistance, being hence validated as a promising therapeutic target. Methods Wildtype PAO1, recycling-defective AmpG and NagZ mutants, an AmpC hyperproducer dacB mutant, and their combinations were used to cause systemic/respiratory infections in mice. Their survival, bacterial burden, inflammation level, and effectiveness of ceftazidime or subtherapeutic colistin to treat the infections were assessed. Results Inactivation of AmpG or NagZ significantly attenuated the virulence in terms of mice mortality, bacterial load, and inflammation. When inactivating these genes in the dacB-defective background, the β-lactam resistance phenotype was abolished, disabling the emergence of ceftazidime-resistant mutants, and restoring ceftazidime for treatment. Subtherapeutic colistin was shown to efficiently clear the infection caused by the recycling-defective strains, likely due to the combined effect with the mice cell-wall– targeting immunity. Conclusions This study brings us one step closer to new therapies intended to disable P. aeruginosa AmpC-mediated resistance and dampen its virulence, and strongly support the interest in developing efficient AmpG and/or NagZ inhibitors.

Funder

Ministerio de Economía y Competitividad of Spain

Instituto de Salud Carlos III

European Regional Development Fund

Servei d'Ocupació de les Illes Balears (SOIB) Jove: Qualificats Sector Públic

Garantía Juvenil

European Social Fund

Publisher

Oxford University Press (OUP)

Subject

Infectious Diseases,Immunology and Allergy

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