Understanding the Phage–Host Interaction Mechanism toward Improving the Efficacy of Current Antibiotics in Mycobacterium abscessus

Author:

Gorzynski Mylene12,De Ville Katalla13,Week Tiana14,Jaramillo Tiana15,Danelishvili Lia12ORCID

Affiliation:

1. Department of Biomedical Sciences, Carlson College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA

2. Department of Microbiology, College of Science, Oregon State University, Corvallis, OR 97331, USA

3. Department of Biochemistry & Molecular Biology, College of Science, Oregon State University, Corvallis, OR 97331, USA

4. Department of Bioengineering, College of Engineering, Oregon State University, Corvallis, OR 97331, USA

5. Department of Animal Sciences, College of Agricultural Sciences, Oregon State University, Corvallis, OR 97331, USA

Abstract

Pulmonary infections caused by Mycobacterium abscessus (MAB) have been increasing in incidence in recent years, leading to chronic and many times fatal infections due to MAB’s natural resistance to most available antimicrobials. The use of bacteriophages (phages) in clinics is emerging as a novel treatment strategy to save the lives of patients suffering from drug-resistant, chronic, and disseminated infections. The substantial research indicates that phage–antibiotic combination therapy can display synergy and be clinically more effective than phage therapy alone. However, there is limited knowledge in the understanding of the molecular mechanisms in phage–mycobacteria interaction and the synergism of phage–antibiotic combinations. We generated the lytic mycobacteriophage library and studied phage specificity and the host range in MAB clinical isolates and characterized the phage’s ability to lyse the pathogen under various environmental and mammalian host stress conditions. Our results indicate that phage lytic efficiency is altered by environmental conditions, especially in conditions of biofilm and intracellular states of MAB. By utilizing the MAB gene knockout mutants of the MAB_0937c/MmpL10 drug efflux pump and MAB_0939/pks polyketide synthase enzyme, we discovered the surface glycolipid diacyltrehalose/polyacyltrehalose (DAT/PAT) as one of the major primary phage receptors in mycobacteria. We also established a set of phages that alter the MmpL10 multidrug efflux pump function in MAB through an evolutionary trade-off mechanism. The combination of these phages with antibiotics significantly decreases the number of viable bacteria when compared to phage or antibiotic-alone treatments. This study deepens our understanding of phage–mycobacteria interaction mechanisms and identifies therapeutic phages that can lower bacterial fitness by impairing an antibiotic efflux function and attenuating the MAB intrinsic resistance mechanism via targeted therapy.

Funder

Animal Health and Disease Research program, USDA National Institute of Food and Agriculture

Publisher

MDPI AG

Subject

General Biochemistry, Genetics and Molecular Biology,Medicine (miscellaneous)

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