Emergence of a Globally Dominant IncHI1 Plasmid Type Associated with Multiple Drug Resistant Typhoid

Abstract

Typhoid fever, caused by Salmonella enterica serovar Typhi (S. Typhi), remains a serious global health concern. Since their emergence in the mid-1970s multi-drug resistant (MDR) S. Typhi now dominate drug sensitive equivalents in many regions. MDR in S. Typhi is almost exclusively conferred by self-transmissible IncHI1 plasmids carrying a suite of antimicrobial resistance genes. We identified over 300 single nucleotide polymorphisms (SNPs) within conserved regions of the IncHI1 plasmid, and genotyped both plasmid and chromosomal SNPs in over 450 S. Typhi dating back to 1958. Prior to 1995, a variety of IncHI1 plasmid types were detected in distinct S. Typhi haplotypes. Highly similar plasmids were detected in co-circulating S. Typhi haplotypes, indicative of plasmid transfer. In contrast, from 1995 onwards, 98% of MDR S. Typhi were plasmid sequence type 6 (PST6) and S. Typhi haplotype H58, indicating recent global spread of a dominant MDR clone. To investigate whether PST6 conferred a selective advantage compared to other IncHI1 plasmids, we used a phenotyping array to compare the impact of IncHI1 PST6 and PST1 plasmids in a common S. Typhi host. The PST6 plasmid conferred the ability to grow in high salt medium (4.7% NaCl), which we demonstrate is due to the presence in PST6 of the Tn6062 transposon encoding BetU.

Genomic Signature of Multidrug-Resistant Salmonella enterica Serovar Typhi Isolates Related to a Massive Outbreak in Zambia between 2010 and 2012

“…A similar resistance pattern has also been described to be emerging around the world (34,48,49). Additionally, a high level of resistance in S. Typhi to quinolones and fluoroquinolones, including resistance resulting from single mutations in the QRDR of the gyrA gene, has also been reported (1,34,42,49,50). In this study, we found 4.3% of the isolates being classified as nalidixic acid resistant due to single mutations in gyrA at codon Ser83 or codon Asp87.…”

MinION nanopore sequencing identifies the position and structure of a bacterial antibiotic resistance island

“…3a,b) demonstrated that, although the island shares several features with both plasmids, the lack of absolute similarity suggests it did not come directly from either, but rather, all three have a common source that is currently undefined. The evolutionary process leading to the emergence of H58 has involved bacterial host-plasmid adaptation causing a reduction in biological cost of the resistance phenotype 13 and now, as we have demonstrated, chromosomal integration of a set of genes. These genes have no obvious source, and the similarity of the island to a plasmid identified in sewage has opened up our research into the island's origins.…”

Antimicrobial Resistance in Salmonella enterica Serovar Typhi Isolates from Bangladesh, Indonesia, Taiwan, and Vietnam

“…The resistances to the 6 drugs were associated with the resistance genes bla TEM-1 , catA1, strA-strB, sul1, sul2, tetA, tetA(B), and dfrA7, which are frequently carried on IncHI1 plasmids (13). This plasmid type is frequently associated with globally spread MDR S. Typhi and MDR S. Paratyphi A (15,16). In this study, all MDR isolates and a tetracycline-resistant isolate from Vietnam carried IncHI1 plasmids, whereas only 4 of the 26 MDR isolates from Bangladesh carried an IncHI1-type plasmid (Table 2).…”