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Environmental structure drives resistance to phages and antibiotics during phage therapy and to invading lysogens during colonisation.

ABSTRACT: Microbial communities are shaped by bacteriophages through predation and lysogeny. A better understanding of the interactions between these processes across different types of environments is key to elucidate how phages mediate microbial competition and to design efficient phage therapies. We introduce an individual-based model (eVIVALDI) to investigate the role of environmental structure in the elimination of a population with a combined treatment of antibiotics and virulent phages, and in the invasion of a population of phage-sensitive bacteria by lysogens. We show that structured environments facilitate the emergence of double resistance, to antibiotics and phages, due to limited diffusion of phage particles and increased nutrient availability from dead cells. They also hinder phage amplification, thus decreasing the generation of phage genetic diversity and increasing the unpredictability of phage-bacteria arms-races. We used a machine learning approach to determine the variables most important for the invasion of sensitive populations by lysogens. They revealed that phage-associated traits and environmental structure are the key drivers of the process. Structured environments hinder invasions, and accounting for their existence improves the fit of the model to published in vivo experimental data. Our results underline environmental structure as key to understand in vivo phage-bacteria interactions.

SUBMITTER: Sousa JAM

PROVIDER: S-EPMC6395636 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Project description:Mycobacterium abscessus is an opportunistic pathogen whose treatment is confounded by widespread multidrug resistance. The therapeutic use of bacteriophages against Mycobacterium abscessus infections offers a potential alternative approach, although the spectrum of phage susceptibilities among M. abscessus isolates is not known. We determined the phage infection profiles of 82 M. abscessus recent clinical isolates and find that colony morphotype-rough or smooth-is a key indicator of phage susceptibility. None of the smooth strains are efficiently killed by any phages, whereas 80% of rough strains are infected and efficiently killed by at least one phage. The repertoire of phages available for potential therapy of rough morphotype infections includes those with relatively broad host ranges, host range mutants of Mycobacterium smegmatis phages, and lytically propagated viruses derived from integrated prophages. The rough colony morphotype results from indels in the glycopeptidolipid synthesis genes mps1 and mps2, negating reversion to smooth as a common route to phage resistance. Resistance is thus rare, and although mutations in polyketide synthesis, uvrD2, and rpoZ can confer resistance, these likely also impair survival in vivo The expanded therapeutic repertoire and the resistance profiles show that small cocktails or single phages could be suitable for controlling infections with rough strains.IMPORTANCEMycobacterium abscessus infections in cystic fibrosis patients are challenging to treat due to widespread antibiotic resistance. The therapeutic use of lytic bacteriophages presents a new potential strategy, but the great variation among clinical M. abscessus isolates demands determination of phage susceptibility prior to therapy. Elucidation of the variation in phage infection and factors determining it, expansion of the suite of therapeutic phage candidates, and a greater understanding of phage resistance mechanisms substantially advances the potential for broad implementation of new therapeutic options for M. abscessus infections.

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Environmental structure drives resistance to phages and antibiotics during phage therapy and to invading lysogens during colonisation.

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