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Evolution of Antibiotic Tolerance Shapes Resistance Development in Chronic Pseudomonas aeruginosa Infections

Santi, Isabella and Manfredi, Pablo and Maffei, Enea and Egli, Adrian and Jenal, Urs. (2021) Evolution of Antibiotic Tolerance Shapes Resistance Development in Chronic Pseudomonas aeruginosa Infections. mBio, 12 (1). e03482-20.

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Official URL: https://edoc.unibas.ch/82295/

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Abstract

The widespread use of antibiotics promotes the evolution and dissemination of resistance and tolerance mechanisms. To assess the relevance of tolerance and its implications for resistance development, we used; in vitro; evolution and analyzed the inpatient microevolution of; Pseudomonas aeruginosa; , an important human pathogen causing acute and chronic infections. We show that the development of tolerance precedes and promotes the acquisition of resistance; in vitro; , and we present evidence that similar processes shape antibiotic exposure in human patients. Our data suggest that during chronic infections,; P. aeruginosa; first acquires moderate drug tolerance before following distinct evolutionary trajectories that lead to high-level multidrug tolerance or to antibiotic resistance. Our studies propose that the development of antibiotic tolerance predisposes bacteria for the acquisition of resistance at early stages of infection and that both mechanisms independently promote bacterial survival during antibiotic treatment at later stages of chronic infections.; IMPORTANCE; Over the past decades, pan-resistant strains of major bacterial pathogens have emerged and have rendered clinically available antibiotics ineffective, putting at risk many of the major achievements of modern medicine, including surgery, cancer therapy, and organ transplantation. A thorough understanding of processes leading to the development of antibiotic resistance in human patients is thus urgently needed. We show that drug tolerance, the ability of bacteria to survive prolonged exposure to bactericidal antibiotics, rapidly evolves in the opportunistic human pathogen; Pseudomonas aeruginosa; upon recurrent exposures to antibiotics. Our studies show that tolerance protects; P. aeruginosa; against different classes of antibiotics and that it generally precedes and promotes resistance development. The rapid evolution of tolerance during treatment regimens may thus act as a strong driving force to accelerate antibiotic resistance development. To successfully counter resistance, diagnostic measures and novel treatment strategies will need to incorporate the important role of antibiotic tolerance.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Growth & Development
05 Faculty of Science > Departement Biozentrum > Infection Biology > Molecular Microbiology (Jenal)
05 Faculty of Science > Departement Biozentrum > Growth & Development > Molecular Microbiology (Jenal)
05 Faculty of Science > Departement Biozentrum > Infection Biology
UniBasel Contributors:Jenal, Urs
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Society for Microbiology
ISSN:2150-7511
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
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edoc DOI:
Last Modified:17 Mar 2021 14:03
Deposited On:17 Mar 2021 14:03

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