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Multiple drug (antibiotic) resistance (MDR) has become a major threat to the treatment of typhoid and other infectious diseases. Since the 1970s, this threat has increased in Salmonella enterica serovar Typhi, driven in part by the emergence of successful genetic clades, such as haplotype H58, associated with the MDR phenotype. H58 S. Typhi can express multiple antibiotic resistance determinants while retaining the ability to efficiently transmit and persist within the human population. The recent identification of extensively drug resistant S. Typhi only highlights the dangers of ignoring this threat. Here we discuss the evolution of the S. Typhi MDR phenotype and consider options for management.

Understanding the dynamics of infection and carriage of typhoid in endemic settings is critical to finding solutions to prevention and control. In a 3-year case-control study, we investigated typhoid among children aged <16 years (4670 febrile cases and 8549 age matched controls) living in an informal settlement, Nairobi, Kenya. 148 . Typhi isolates from cases and 95 from controls (stool culture) were identified; a carriage frequency of 1 %. Whole-genome sequencing showed 97% of cases and 88% of controls were genotype 4.3.1 (Haplotype 58), with the majority of each (76% and 88%) being multidrug-resistant strains in three sublineages of the H58 genotype (East Africa 1 (EA1), EA2, and EA3), with sequences from cases and carriers intermingled. The high rate of multidrug-resistant H58 . Typhi, and the close phylogenetic relationships between cases and controls, provides evidence for the role of carriers as a reservoir for the community spread of typhoid in this setting. National Institutes of Health (R01AI099525); Wellcome Trust (106158/Z/14/Z); European Commission (TyphiNET No 845681); National Institute for Health Research (NIHR); Bill and Melinda Gates Foundation (OPP1175797).

Salmonella enterica serovar Typhi H58, an antimicrobial-resistant lineage, is globally disseminated but has not been reported in Latin America. Genomic analysis revealed 3 independent introductions of Salmonella Typhi H58 with reduced fluoroquinolone susceptibility into Chile. Our findings highlight the utility of enhanced genomic surveillance for typhoid fever in this region.

In this study, we examined the clinically relevant, multi-drug resistant Salmonella Typhi strain H58, which is rapidly disseminating across Southeast Asia, Africa, and Oceania. It has heretofore been uncharacterized in terms of its gene regulation. Using human THP-1 macrophages, we discovered that S. Typhi strongly activates the sulfur utilization pathway in response to acid stress encountered in the vacuole once Typhi is inside host cells. Our novel findings were that S. Typhi experiences substantially higher redox stress compared with Typhimurium, and it requires the sulfur utilization pathway to mitigate this stress. This pathway is not upregulated in Typhimurium and represents a divergence in the response of these two serovars. We emphasize that S. Typhimurium is not a reasonable model for understanding H58, a serovar that is seriously impacting human health.

PurposeThe efficacy of drugs against Salmonella infection have compromised due to emerging XDR H58 strain. There is a dire need to find novel antimicrobial drug targets as well as drug candidates to cure by the XDR strain of Salmonella. It is observed that the complete genome sequence of the XDR H58 strain contains a large number of hypothetical proteins with unknown cellular and biological functions. Hence, it is indispensable to annotate these proteins functionally as well as structurally to identify novel drug targets.MethodsIn the current study, a comparative genomics and proteomics based approach was applied to find the novel drug targets in XDR strain while comparing the MDR and NR strains of Salmonella typhi.ResultsThe characterization of ~ 350 hypothetical proteins were performed through determination of their physio-chemical properties, sub-cellular localization, functional annotation, and structure-based studies. As a result, only five proteins were prioritized as essential, druggable, and virulent proteins. Moreover, only one protein i.e. WP_000916613.1 was functionally annotated with high confidence and subjected to further structure-based analysis.ConclusionThe current study presents a hypothetical protein from the XDR S. typhi proteome as a potential pharmacological target against which novel therapeutic candidates may be predicted. The outcome of the current study may lead to formulate a general set of pipelines for better understanding of the role of hypothetical proteins in pathogenesis of not only Salmonella but also for other pathogens.

Background. Multiyear epidemics of Salmonella enterica serovar Typhi have been reported from countries across eastern and southern Africa in recent years. In Blantyre, Malawi, a dramatic increase in typhoid fever cases has recently occurred, and may be linked to the emergence of the H58 haplotype. Strains belonging to the H58 haplotype often exhibit multidrug resistance and may have a fitness advantage relative to other Salmonella Typhi strains. Methods. To explore hypotheses for the increased number of typhoid fever cases in Blantyre, we fit a mathematical model to culture-confirmed cases of Salmonella enterica infections at Queen Elizabeth Central Hospital, Blantyre. We explored 4 hypotheses: (1) an increase in the basic reproductive number (R0) in response to increasing population density; (2) a decrease in the incidence of cross-immunizing infection with Salmonella Enteritidis; (3) an increase in the duration of infectiousness due to failure to respond to first-line antibiotics; and (4) an increase in the transmission rate following the emergence of the H58 haplotype. Results. Increasing population density or decreasing cross-immunity could not fully explain the observed pattern of typhoid emergence in Blantyre, whereas models allowing for an increase in the duration of infectiousness and/or the transmission rate of typhoid following the emergence of the H58 haplotype provided a good fit to the data. Conclusions. Our results suggest that an increase in the transmissibility of typhoid due to the emergence of drug resistance associated with the H58 haplotype may help to explain recent outbreaks of typhoid in Malawi and similar settings in Africa.

The interplay between bacterial antimicrobial susceptibility, phylogenetics and patient outcome is poorly understood. During a typhoid clinical treatment trial in Nepal, we observed several treatment failures and isolated highly fluoroquinolone-resistant Salmonella Typhi (S. Typhi). Seventy-eight S. Typhi isolates were genome sequenced and clinical observations, treatment failures and fever clearance times (FCTs) were stratified by lineage. Most fluoroquinolone-resistant S. Typhi belonged to a specific H58 subclade. Treatment failure with S. Typhi-H58 was significantly less frequent with ceftriaxone (3/31; 9.7%) than gatifloxacin (15/34; 44.1%)(Hazard Ratio 0.19, p=0.002). Further, for gatifloxacin-treated patients, those infected with fluoroquinolone-resistant organisms had significantly higher median FCTs (8.2 days) than those infected with susceptible (2.96) or intermediately resistant organisms (4.01)(p<0.001). H58 is the dominant S. Typhi clade internationally, but there are no data regarding disease outcome with this organism. We report an emergent new subclade of S. Typhi-H58 that is associated with fluoroquinolone treatment failure. Clinical trial registration: ISRCTN63006567. People who ingest a type of bacteria called Salmonella Typhi can develop the symptoms of typhoid fever. This disease is common in low-income settings in Asia and Africa, and causes a high rate of death in people who are not treated with antimicrobial drugs. During a study in Nepal, Thanh et al. tried to evaluate which of two antimicrobials was better for treating typhoid fever. One of the drugs – called gatifloxacin – did not work in some of the patients. To understand why this treatment failed, Thanh et al. decoded the entire DNA sequences of all the Salmonella Typhi bacteria isolated during the study. Comparing this genetic data to the clinical data of the patients identified a new variant of Salmonella Typhi. These bacteria have a specific combination of genetic mutations that render them resistant to the family of drugs that gatifloxacin belongs to – the fluoroquinolones. Patients infected with the variant bacteria and treated with gatifloxacin were highly likely to completely fail treatment and have longer-lasting fevers. On further investigation Thanh et al. found these organisms were likely recently introduced into Nepal from India. Fluoroquinolones are amongst the most effective and common antimicrobials used to treat typhoid fever and other bacterial infections. However, the presence of bacteria that are resistant to these compounds in South Asia means that they should no longer be the first choice of drug to treat typhoid fever in this location.

Little genomic data is available for typhoid fever from island nations, though the disease has a moderately high burden there. Sikorski et al. (M. J. Sikorski, T. H. Hazen, S. N. Desai, S. Nimarota-Brown, et al., mBio 13:e01920-22, 2022, https://doi.org/10.1128/mbio.01920-22 ) studied 306 Salmonella enterica serovar Typhi genomes from the Samoan Islands collected during 1983 to 2020 and reported dominance of a rare genotype, 3.5.4, and no H58 (genotype 4.3.1). Little genomic data is available for typhoid fever from island nations, though the disease has a moderately high burden there. Sikorski et al. (M. J. Sikorski, T. H. Hazen, S. N. Desai, S. Nimarota-Brown, et al., mBio 13:e01920-22, 2022, https://doi.org/10.1128/mbio.01920-22 ) studied 306 Salmonella enterica serovar Typhi genomes from the Samoan Islands collected during 1983 to 2020 and reported dominance of a rare genotype, 3.5.4, and no H58 (genotype 4.3.1). They found pansusceptibility of all isolates to three first lines of antimicrobial agents (ampicillin, chloramphenicol, and cotrimoxazole). This commentary evaluates the importance of these findings for the Samoan Islands and how they can help the global typhoid community. The microbial community in the environment and human gut could have played a role in the lack of antimicrobial resistance (AMR). However, drug-resistant strains may arrive soon at the island, as their international spread is common. Further investigation would help the global typhoid community to better understand the evolution of an isolated pathogen community and the effect of vaccination there.

Typhoid fever is caused by a pathogenic, rod-shaped, flagellated, and Gram-negative bacterium known as Salmonella Typhi. It features a polysaccharide capsule that acts as a virulence factor and deceives the host immune system by protecting phagocytosis. Typhoid fever remains a major health concern in low and middle-income countries, with an estimated death rate of ~200,000 per annum. However, the situation is exacerbated by the emergence of the extensively drug-resistant (XDR) strain designated as H58 of S. Typhi. The emergence of the XDR strain is alarming, and it poses serious threats to public health due to the failure of the current therapeutic regimen. A relatively newer computational method called subtractive genomics analyses has been widely applied to discover novel and new drug targets against pathogens, particularly drug-resistant ones. The method involves the gradual reduction of the complete proteome of the pathogen, leading to few potential and novel drug targets. Thus, in the current study, a subtractive genomics approach was applied against the Salmonella XDR strain to identify potential drug targets. The current study predicted four prioritized proteins (i.e., Colanic acid biosynthesis acetyltransferase wcaB, Shikimate dehydrogenase aroE, multidrug efflux RND transporter permease subunit MdtC, and pantothenate synthetase panC) as potential drug targets. Though few of the prioritized proteins are treated in the literature as the established drug targets against other pathogenic bacteria, these drug targets are identified here for the first time against S. Typhi (i.e., S. Typhi XDR). The current study aimed at drawing attention to new drug targets against S. Typhi that remain largely unexplored. One of the prioritized drug targets, i.e., Colanic acid biosynthesis acetyltransferase, was predicted as a unique, new drug target against S. Typhi XDR. Therefore, the Colanic acid was further explored using structure-based techniques. Additionally, ~1000 natural compounds were docked with Colanic acid biosynthesis acetyltransferase, resulting in the prediction of seven compounds as potential lead candidates against the S. Typhi XDR strain. The ADMET properties and binding energies via the docking program of these seven compounds characterized them as novel drug candidates. They may potentially be used for the development of future drugs in the treatment of Typhoid fever.

Typhoid fever is a notable disease in Hong Kong. We noticed two local cases of typhoid fever caused by Salmonella Typhi within a two-week period in late 2022, which had no apparent epidemiological linkage except for residing in the same region of Hong Kong. A phylogenetic study of Salmonella Typhi isolates from Hong Kong Island from 2020 to 2022 was performed, including a whole-genome analysis, the typing of plasmids, and the analysis of antibiotic-resistance genes (ARGs), to identify the dominant circulating strain and the spread of ARGs. A total of seven isolates, from six local cases and an imported case, were identified from positive blood cultures in two hospitals in Hong Kong. Five antibiotic-sensitive strains of genotype 3.2.2 were found, which clustered with another 30 strains originating from Southeast Asia. Whole-genome sequencing revealed clonal transmission between the two index cases. The remaining two local cases belong to genotype 2.3.4 and genotype 4.3.1.1.P1 (also known as the H58 lineage). The genotype 4.3.1.1.P1 strain has an extensively drug-resistant (XDR) phenotype (co-resistance to ampicillin, chloramphenicol, ceftriaxone, ciprofloxacin, and co-trimoxazole). Although the majority of local strains belong to the non-H58 genotype 3.2.2 with a low degree of antibiotic resistance, the introduction of XDR strains with the global dissemination of the H58 lineage remains a concern.