Collateral sensitivity increases the efficacy of a rationally designed bacteriophage combination to controlSalmonella enterica

Abstract

AbstractThe ability of virulent bacteriophages to lyse bacteria influences bacterial evolution, fitness, and population structure. Knowledge of both host susceptibility and resistance factors is crucial for the successful application of bacteriophages as biological control agents in clinical therapy, food processing and agriculture. In this study, we isolated twelve bacteriophages termed SPLA phage which infect the foodborne pathogenSalmonella enterica. To determine phage host range, a diverse collection ofEnterobacteriaceaeandSalmonella entericawere used and genes involved in infection by six SPLA phages were identified usingSalmonellaTyphimurium strain ST4/74. Candidate host receptors included lipopolysaccharide, cellulose and BtuB. Lipopolysaccharide was identified as susceptibility factor for phage SPLA1a and mutations in LPS biosynthesis genes spontaneously emerged during culture withS. Typhimurium. Conversely, LPS was a resistance factor for phage SPLA5b that suggested that emergence of LPS mutations in culture with SPLA1a may represent a case of collateral sensitivity to SPLA5b. We show that combination therapy with SPLA1a and SPLA5b was more successful in limiting the emergence of phage resistance compared to monotherapy. Identification of host susceptibility and resistance genes and understanding infection dynamics is critical step in rationale design of phage cocktails against specific bacterial pathogens.