Salmonella Typhi acquires diverse plasmids from other Enterobacteriaceae to develop cephalosporin resistance

Abstract Background Recent reports have established the emergence and dissemination of extensively drug resistant (XDR) H58 Salmonella Typhi clone in Pakistan. In India where typhoid fever is endemic, only sporadic cases of ceftriaxone resistant S . Typhi are reported. This study aimed at elucidating the phylogenetic evolutionary framework of ceftriaxone resistant S . Typhi isolates from India to predict their potential dissemination in endemic regions. Methods Five ceftriaxone resistant S . Typhi isolates from three tertiary care hospitals in India were sequenced on an Ion Torrent Personal Genome Machine (PGM). A core genome single-nucleotide-polymorphism (SNP) based phylogeny of the isolates in comparison to the global collection of MDR and XDR S . Typhi isolates was built. Two of five isolates were additionally sequenced using Oxford Nanopore MinION to completely characterize the plasmid and understand its transmission dynamics within Enterobacteriaceae. Results Comparative genomic analysis and detailed plasmid characterization indicate that while in Pakistan (4.3.1 lineage I) the XDR trait is associated with bla CTX-M-15 gene on IncY plasmid, in India (4.3.1 lineage II), the ceftriaxone resistance is due to short term adaptation of resistance plasmids such as IncX3 or IncN. Conclusion Since the bacterial acquisition of smaller resistance plasmids such as IncX3 or IncN from other Enterobacteriaceae can be much faster than the larger IncY plasmids, the rapid expansion of these genotypically novel XDR S . Typhi could potentially cause large outbreaks. Therefore, continuous monitoring of S . Typhi lineages carrying cephalosporin resistance on IncX3 or IncN plasmids is vital not just for India but globally. Importance Genomic analysis of cephalosporin resistant S . Typhi isolated from India indicates the potential of S . Typhi to develop cephalosporin resistance by acquiring diverse plasmids from other Enterobacteriaceae. We identified the occurrence of independent acquisition of drug-resistant plasmids such as IncX3 and IncN with genes encoding beta-lactamases in H58/4.3.1.2 lineage. A short term adaptation of drug-resistant plasmids in H58/4.3.1.2 lineage can be the reason for the sporadic cases cephalosporin resistant S . Typhi in India. However, the IncY plasmid acquired by isolates that belong to H58/4.3.1.1 lineage appeared to be well adapted as observed in XDR S. Typhi outbreak in Pakistan. Plasmid acquisition and maintenance of cephalosporin resistant S . Typhi appears to be specific to the phylogenetic lineage as lineages differ in compensating the initial cost imposed by the plasmid. The stable maintenance of these resistance plasmids without a fitness cost, are determinant in understanding the future spread of cephalosporin resistance in S . Typhi. Therefore, critical strategies in monitoring and control of cephalosporin resistant S . Typhi is needed to tackle further public health crisis.