Comparative genomic analysis reveals the basis of phage susceptibility among Salmonella Typhimurium DT104 and DT104b

Worldwide, infections caused by non-typhoidal Salmonella enterica serovar Typhimurium phage types DT104 and DT104b represent a significant public health concern and an economic burden that is substantially exacerbated by antibiotic resistance. Commonly resistant to ampicillin, chloramphenicol, streptomycin, sulphonamides and tetracycline (ACSSuT resistance profile), S. Typhimurium DT104 and DT104b increasingly become resistant to other antimicrobial agents of clinical importance, such as ciprofloxacin (EFSA and ECDC, 2020). The surge in mortality and morbidity rates, caused by multi-resistant bacteria, prompted a renewal of interest to phages as clinical therapeutics and natural biocontrol agents. Nevertheless, bacteria and phages are continually under the pressure of the evolutionary phage-host arms race for the survival, which is mediated by the co-evolving resistance mechanisms (Sillankorva et al., 2012; Food Standards Agency, 2016; Orzechowska and Mohammed, 2019). Until recently, surveillance and outbreak investigation of S. Typhimurium was performed by phage typing; however, Whole Genome Sequencing (WGS), enabling comprehensive in silico study of microorganisms, began replacing the phenotypic characterisation (Baggesen et al., 2010; Ashton et al., 2015; Kwong et al., 2015). In the Anderson et al. phage typing scheme (1977), the epidemiologically related S. Typhimurium DT104 and DT104b display significantly different phage susceptibility profiles (Table 1). This pilot study aimed to characterise phage resistance mechanisms and genomic differences that may be responsible for the divergent phage reaction patterns in S. Typhimurium DT104 and DT104b. A repertoire of known anti-phage mechanisms was studied, including prophages, restriction-modification (R-M) systems and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) along with CRISPR-associated (Cas) proteins