Korbsrisate, S. | Search bioRxiv

bioRxiv2026

Cellular heterogeneity in the response of Burkholderia thailandensis to antibiotics and phages in synthetic spatial refuges

Understanding the complex interactions between phage, antibiotics and bacteria is vital for the development of rationale phage-antibiotic therapies. These interactions have traditionally been investigated via bulk assays, thus masking eventual cellular heterogeneities and the impact of spatial refuges on phage and antibiotic efficacy. Using microfluidics-based time-lapse microscopy, we reveal large phenotypic heterogeneity in the response of Burkholderia thailandensis to both the bacteriophage {Phi}Bp-AMP1 and sub-inhibitory concentrations of two selected antibiotics ciprofloxacin and trimethoprim. We discover that simultaneous exposure to ciprofloxacin and phage decreases the size of individual B. thailandensis cells, whereas phage and trimethoprim together slow down cell doubling. Exposure to ciprofloxacin also causes extended phage lysis of B. thailandensis which is preceded by a distinguishable pause in cell elongation, whereas exposure to trimethoprim constrains lysis. As a consequence, exposure to ciprofloxacin further hinders the growth of B. thailandensis in the presence of phage, whereas exposure to trimethoprim enhances growth in the presence of phage. These findings help understand the effects of the interactions between antibiotics and phage on bacterial subpopulations in spatial refuges that are notoriously difficult to treat with antibiotics.

microbiology↗

bioRxiv2023

Phage-induced efflux down-regulation boosts antibiotic efficacy

The interactions between a virus and its host vary in space and time and are affected by the presence of molecules that alter the physiology of either the host or the virus. Determining the molecular mechanisms underpinning these interactions is paramount for predicting the fate of bacterial and phage populations and for designing rational phage-antibiotic therapies. We study the interactions between stationary phase Burkholderia thailandensis and the phage {Phi}Bp-AMP1. Although heterogeneous genetic resistance to phage rapidly emerges in B. thailandensis, the presence of phage enhances the efficacy of three major antibiotic classes, the quinolones, the beta-lactams and the tetracyclines, but antagonizes tetrahydrofolate synthesis inhibitors. We discovered that enhanced antibiotic efficacy is underpinned by reduced antibiotic efflux in the presence of phage. This new phage-antibiotic therapy allows for eradication of stationary phase bacteria, whilst requiring reduced antibiotic concentrations, which is crucial for treating infections in sites where it is difficult to achieve high antibiotic concentrations.

microbiology↗