Bacteriophage-Insensitive Mutants of Antimicrobial-Resistant Salmonella Enterica are Altered in their Tetracycline Resistance and Virulence in Caco-2 Intestinal Cells

Abstract

Bacteriophages have shown promise as therapeutic alternatives to antibiotics for the control of infectious bacteria, including the human pathogen Salmonella. However, the development of effective phage-based applications requires the elucidation of key interactions between phages and target hosts, particularly since host resistance to phage is inevitable. Little is known about the alteration of host phenotypes following the development of resistance to phage. The aim of this study is to evaluate the antibiotic susceptibility and virulence of a Salmonella isolate following the development of resistance to bacteriophage SI1. We observed enhanced susceptibility to tetracycline and decreased invasion capacity in a differentiated Caco-2 intestinal cell line. Whole genome sequence analysis revealed an array of mutations, most notably, truncations in vgrG1_2, a core gene involved in Type VI secretion and mutations in the lipopolysaccharide, thereby indicating the plausible attachment site of phage SI1. These findings shed light on understanding the underlying mechanism for phage immunity within the host. Importantly, we reveal an associated genetic cost to the bacterial host with developing resistance to phages. Taken together, these results will aid in advancing strategies to delay or eliminate the development of host resistance when designing informed phage-based antimicrobials.

Characterization of vB_Sau_S90, and vB_Sau_S165, a Broad Host Range Phages, and Multiple Phage Doses as a Potential Therapeutic Strategy to Eliminate Transient Phage Resistant Mutants in Staphylococcus Aureus

“…Interestingly, we found that no stable phage-resistant mutants appeared for both the phages studied as regrowing bacterial cells lost resistance to phage with a maximum of two serial passages, thus showing the presence of transient phage resistant mutants. Similar observations were noted in Salmonella enterica by Fong et al, in which most of the transient phage-resistant mutants isolated become susceptible to serial passage (Fong et al 2020).…”

An Optimized Bacteriophage Cocktail Can Effectively Control Salmonella in vitro and in Galleria mellonella

“…As a result, a number of trade restrictions are introduced in cases where there is contamination with prevalent serotypes of S. Enteritidis and S. Typhimurium leading to major loss of income to farmers and producers due to rejection of substandard contaminated animal products ( Majowicz et al, 2010 ; Kirk et al, 2015 ; EFSA Panel on Biological Hazards et al, 2019 ). Although antibiotics are useful in controlling the infection in both humans and animals, many of the bacterial strains are becoming resistant to routinely used antibiotics leading to treatment failure and disease outbreaks ( O’Neil, 2014 ; Fong et al, 2020 ). As the identification and development of new antibiotics is slow and difficult, the associated economic and social loss highlight the pressing need to develop alternative more effective therapeutics for this infection ( O’Neil, 2014 ; Romero-Calle et al, 2019 ).…”

Prophage Diversity Across Salmonella and Verotoxin-Producing Escherichia coli in Agricultural Niches of British Columbia, Canada

“…The growing inadequacy of antibiotics has paved the way for novel therapies that rely on antibiotic alternatives. Many studies have focused on application of lytic phages for direct killing of their bacterial hosts, however, host resistance still occurs (Fong et al, 2017(Fong et al, , 2020.…”