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The study revealed the differential ability of cefepime/taniborbactam and cefepime/zidebactam in tackling carbapenemase-producing Indian clinical isolates that also harbored additional mechanisms of resistance. NDM-expressing E. coli with 4-amino-acid insert in PBP3 are predominately resistant to cefepime/taniborbactam, while the β-lactam enhancer mechanism-based cefepime/zidebactam showed consistent activity against single- or dual-carbapenemase-producing isolates including E. coli with PBP3 inserts.

AB toxins have historically been associated with significant morbidity, mortality through infections such as botulinum, anthrax, cholera, and diphtheria. These AB toxin-mediated diseases remain prevalent in low and middle income countries, with intermittent outbreaks of Shiga toxin-producing Escherichia coli (STEC) or whooping cough by Bordetella pertussis in high-income countries. These reports warrant an investigation to better understand the distinct characteristics of AB toxins derived from different pathogens. As toxigenic pathogens broaden their scope and diversity, it amplifies the complexity of the problems posed by their AB toxins. Here, we discuss the history, structure and characteristics of key AB toxins, and report on historical and ongoing research on these toxins. We also explore research avenues that hold great promise in potentially improving clinical management of toxin-mediated diseases in the future.

Background Following a relatively mild first wave of coronavirus disease 2019 (COVID-19) in India, a deadly second wave of the pandemic overwhelmed the healthcare system due to the emergence of fast-transmitting SARS-CoV-2 genetic variants. The emergence and spread of the B.1.617.2/Delta variant considered to be driving the devastating second wave of COVID-19 in India. Currently, the Delta variant has rapidly overtaken the previously circulating variants to become the dominant strain. Critical mutations in the spike/RBD region of these variants have raised serious concerns about the virus's increased transmissibility and decreased vaccine effectiveness. As a result, significant scientific and public concern has been expressed about the impact of virus variants on COVID-19 vaccines. Objectives The purpose of this article is to provide an additional explanation in the context of the evolutionary trajectory of SARS-CoV-2 variants in India, the vaccine-induced immune response to the variants of concern (VOC), and various vaccine deployment strategies to rapidly increase population immunity. Content Phylogenetic analysis of SARS-CoV-2 isolates circulating in India suggests the emergence and spread of B.1.617 variant. The immunogenicity of currently approved vaccines indicates that the majority of vaccines elicit an antibody response and some level of protection. According to current data, vaccines in the pre-fusion configuration (2p substitution) have an advantage in terms of nAb titer, but the duration of vaccine-induced immunity, as well as the role of T cells and memory B cells in protection, remain unknown. Since vaccine efficacy on virus variants is one of the major factors to be considered for achieving herd immunity, existing vaccines need to be improved or effective next-generation vaccines should be developed to cover the new variants of the virus.

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. 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 blaCTX-M-15 gene on IncY plasmid, in India (4.3.1 lineage II), the ceftriaxone resistance is due to short term persistence of resistance plasmids such as IncX3 (blaSHV-12) or IncN (blaTEM-1B + blaDHA-1). Conclusion Considering the selection pressure exerted by the extensive use of ceftriaxone in India, there are potential risks for the occurrence of plasmid transmission events in the predominant H58 lineages. Therefore, continuous monitoring of S. Typhi lineages carrying plasmid-mediated cephalosporin resistant genes is vital not just for India but also globally., Highlights • S. Typhi to develop cephalosporin resistance by acquiring diverse plasmids from other Enterobacteriaceae. • Independent acquisition of drug-resistant plasmids such as IncX3 and IncN with genes encoding beta-lactamases in H58 lineage II of S. Typhi. • A short-term persistence of drug-resistant plasmids in H58 lineage II can be the reason for the sporadic cases cephalosporin resistant S. Typhi in India. • Plasmid acquisition and maintenance of cephalosporin resistant S. Typhi appears to be specific to the phylogenetic lineage. • Critical strategies in monitoring and control of cephalosporin resistant S. Typhi is needed to tackle further public health crisis.

Background: \ud The emergence of increasingly antimicrobial-resistant Salmonella enterica serovar Typhi (S Typhi) threatens to undermine effective treatment and control. Understanding where antimicrobial resistance in S Typhi is emerging and spreading is crucial towards formulating effective control strategies.\ud \ud Methods: \ud In this genomic epidemiology study, we sequenced the genomes of 3489 S Typhi strains isolated from prospective enteric fever surveillance studies in Nepal, Bangladesh, Pakistan, and India (between 2014 and 2019), and combined these with a global collection of 4169 S Typhi genome sequences isolated between 1905 and 2018 to investigate the temporal and geographical patterns of emergence and spread of antimicrobial-resistant S Typhi. We performed non-parametric phylodynamic analyses to characterise changes in the effective population size of fluoroquinolone-resistant, extensively drug-resistant (XDR), and azithromycin-resistant S Typhi over time. We inferred timed phylogenies for the major S Typhi sublineages and used ancestral state reconstruction methods to estimate the frequency and timing of international and intercontinental transfers.\ud \ud Findings: \ud Our analysis revealed a declining trend of multidrug resistant typhoid in south Asia, except for Pakistan, where XDR S Typhi emerged in 2016 and rapidly replaced less-resistant strains. Mutations in the quinolone-resistance determining region (QRDR) of S Typhi have independently arisen and propagated on at least 94 occasions, nearly all occurring in south Asia. Strains with multiple QRDR mutations, including triple mutants with high-level fluoroquinolone resistance, have been increasing in frequency and displacing strains with fewer mutations. Strains containing acrB mutations, conferring azithromycin resistance, emerged in Bangladesh around 2013 and effective population size of these strains has been steadily increasing. We found evidence of frequent international (n=138) and intercontinental transfers (n=59) of antimicrobial-resistant S Typhi, followed by local expansion and replacement of drug-susceptible clades.\ud \ud Interpretation: \ud Independent acquisition of plasmids and homoplastic mutations conferring antimicrobial resistance have occurred repeatedly in multiple lineages of S Typhi, predominantly arising in south Asia before spreading to other regions.\ud \ud Funding: \ud Bill & Melinda Gates Foundation.

Paratyphoid fever caused byS. Paratyphi A is endemic in parts of Asia and Sub-Saharan Africa. The proportion of enteric fever cases caused byS. Paratyphi A has substantially increased, yet only limited data is available on the population structure and genetic diversity of this serovar. We examined the phylogenetic distribution and evolutionary trajectory ofS. Paratyphi A isolates collected as part of the Indian enteric fever surveillance study “Surveillance of Enteric Fever in India (SEFI).” In the study period (2017-2020),S. Paratyphi A comprised 17.6% (441/2503) of total enteric fever cases in India, with the isolates highly susceptible to all the major antibiotics used for treatment except fluoroquinolones. Phylogenetic analysis clustered the globalS. Paratyphi A collection into seven lineages (A-G), and the present study isolates were distributed in lineages A, C and F. Our analysis documented that the genome degradation events and gene acquisitions or losses play a major role in the evolution of newS. Paratyphi A lineages/sub-lineages. A total of 10 pseudogene-forming mutations possibly associated with the emergence of lineages were identified. Pan-genome analysis identified the insertion of P2/PSP3 phage and acquisition of IncX1 plasmid during the selection in 2.3.2/2.3.3 and 1.2.2 genotypes, respectively. We also identified that the six characteristic missense mutations associated with the lipopolysaccharide (LPS) biosynthesis genes ofS. Paratyphi A confer only a low structural impact and would therefore have minimal impact on vaccine effectiveness. SinceS. Paratyphi A is human restricted, high levels of genetic drift are not expected unless these bacteria transmit to naive hosts. However, public-health investigation and intervention by means of genomic surveillance would be continually needed to avoidS. Paratyphi A serovar becoming a public health threat similar to theS. Typhi of today.

Sanitation is a major global challenge that is often addressed at national and international levels, while community opinions and beliefs are neglected. To promote water, sanitation and hygiene (WASH) we organized a cross-cultural knowledge exchange workshop to assess participatory methods for engaging local stakeholders. The workshop included 22 participants from all sectors of society. Practical solutions to sanitation challenges were identified and later shared with a local community. Qualitative and quantitative analyses were used to assess impact and showed participatory methods were highly valued to encourage information sharing among widely varied stakeholders, and that video was a particularly successful approach when engaging with local communities. An 8-month follow-up survey of village members revealed excellent information recall, positive behaviour changes and a desire for future visits. Our evidence suggests that community-based participation helped identify solutions to WASH issues affecting rural communities in resource-poor settings. Engaging in a multicultural knowledge-share was particularly valuable as it enabled participants to recognize they have common challenges and allowed them to share low-cost solutions from their different communities. Our use of video was widely viewed as an ideal means of circulating findings, as it communicated information to people with a wide variety of community roles and to all age groups. Its relevance was increased by adopting a culturally appropriate context by involving local communities in workshop activities. We recommend that research in low- and middle-income countries should be mindful of the environmental context in which WASH is implemented, and encourage acceptance by engaging with communities through the use of varied participatory methods.

Advanced research in health science has broadened our view in approaching and understanding the pathophysiology of diseases and has also revolutionised diagnosis and treatment. Ever since the establishment of Braak’s hypothesis in the propagation of alpha-synuclein from the distant olfactory and enteric nervous system towards the brain in Parkinson’s Disease (PD), studies have explored and revealed the involvement of altered gut microbiota in PD. This review recapitulates the gut microbiome associated with PD severity, duration, motor and non-motor symptoms, and antiparkinsonian treatment from recent literature. Gut microbial signatures in PD are potential predictors of the disease and are speculated to be used in early diagnosis and treatment. In brief, the review also emphasises on implications of the prebiotic, probiotic, faecal microbiota transplantation, and dietary interventions as alternative treatments in modulating the disease symptoms in PD.

The current global pandemic due to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has taken a substantial number of lives across the world. Although few vaccines have been rolled-out, a number of vaccine candidates are still under clinical trials at various pharmaceutical companies and laboratories around the world. Considering the intrinsic nature of viruses in mutating and evolving over time, persistent efforts are needed to develop better vaccine candidates. In this study, various immuno-informatics tools and bioinformatics databases were deployed to derive consensus B-cell and T-cell epitope sequences of SARS-CoV-2 spike glycoprotein. This approach has identified four potential epitopes which have the capability to initiate both antibody and cell-mediated immune responses, are non-allergenic and do not trigger autoimmunity. These peptide sequences were also evaluated to show 99.82% of global population coverage based on the genotypic frequencies of HLA binding alleles for both MHC class-I and class-II and are unique for SARS-CoV-2 isolated from human as a host species. Epitope number 2 alone had a global population coverage of 98.2%. Therefore, we further validated binding and interaction of its constituent T-cell epitopes with their corresponding HLA proteins using molecular docking and molecular dynamics simulation experiments, followed by binding free energy calculations with molecular mechanics Poisson–Boltzmann surface area, essential dynamics analysis and free energy landscape analysis. The immuno-informatics pipeline described and the candidate epitopes discovered herein could have significant impact upon efforts to develop globally effective SARS-CoV-2 vaccines.

The rapid development of COVID-19 vaccines was the result of decades of research to establish flexible vaccine platforms and understand pathogens with pandemic potential, as well as several novel changes to the vaccine discovery and development processes that partnered industry and governments. And while vaccines offer the potential to drastically improve global health, low-and-middle-income countries around the world often experience reduced access to vaccines and reduced vaccine efficacy. Addressing these issues will require novel vaccine approaches and platforms, deeper insight how vaccines mediate protection, and innovative trial designs and models. On June 28–30, 2021, experts in vaccine research, development, manufacturing, and deployment met virtually for the Keystone eSymposium “Innovative Vaccine Approaches” to discuss advances in vaccine research and development.

Helicobacter pylori is a ubiquitous bacterium and contributes significantly to the burden of chronic gastritis, peptic ulcers, and gastric cancer across the world. Adaptive phenotypes and virulence factors in H. pylori are heterogeneous and dynamic. However, limited information is available about the molecular nature of antimicrobial resistance phenotypes and virulence factors of H. pylori strains circulating in India. In the present study, we analyzed the whole genome sequences of 143 H. pylori strains, of which 32 are isolated from two different regions (eastern and southern) of India. Genomic repertoires of individual strains show distinct region-specific signatures. We observed lower resistance phenotypes and genotypes in the East Indian (Kolkata) H. pylori isolates against amoxicillin and furazolidone antibiotics, whereas higher resistance phenotypes to metronidazole and clarithromycin. Also, at molecular level, a greater number of AMR genes were observed in the east Indian H. pylori isolates as compared to the southern Indian isolates. From our findings, we suggest that metronidazole and clarithromycin antibiotics should be used judicially in the eastern India. However, no horizontally acquired antimicrobial resistance gene was observed in the current H. pylori strains. The comparative genome analysis shows that the number of genes involved in virulence, disease and resistance of H. pylori isolated from two different regions of India is significantly different. Single-nucleotide polymorphisms (SNPs) based phylogenetic analysis distinguished H. pylori strains into different clades according to their geographical locations. Conditionally beneficial functions including antibiotic resistance phenotypes that are linked with faster evolution rates in the Indian isolates.

BackgroundEscherichia coli (ETEC) are one of the top causes of diarrhoea in children in low- and middle-income countries (LMICs). However, large-scale pathogen burden studies in children have identified ETEC in the guts of symptomatic patients and controls. The factors that influence this balance between carriage and disease are poorly understood, but it is postulated that the gut microbiome may play a role in either resistance or progression to disease. In this study, we investigated the microbiome profiles, using shotgun DNA sequencing, of children and adults from Bangladesh who were asymptomatically or symptomatically infected with ETEC. ResultsSymptomatic patients had significantly higher numbers of sequenced reads mapping to both E. coli and the two ETEC toxins (LT and ST), suggesting higher bacterial burden. They were also significantly more likely to be co-infected with enteroaggregative E. coli (EAEC) and had higher proportions of other Gammaproteobacteria, including Klebsiella, Salmonella, and Haemophilus. Colonisation with ETEC (symptomatic or asymptomatic) was also associated with increased prevalence of antimicrobial resistance (AMR) genes, most notably those of the b-lactamase class. Taxonomic profiles were distinctly different between all groups in both species richness (alpha diversity) and composition (beta diversity), although the direction of these changes was different in adults and children. As seen in previous studies, children with high E. coli burdens also had higher proportions of Streptococcus spp., while healthy children were more heavily colonised by several Bifidobacterium spp. ConclusionsOur study provides insight into the microbiome changes that occur upon infection with ETEC in an endemic setting, and provides rationale for future studies investigating how the microbiome may protect or predispose individuals to symptomatic infections with gastrointestinal pathogens.

We investigated the evolution, phylogeny and antimicrobial resistance of Vibrio cholerae O1 isolates (VCO1) from Ghana. Outbreak and environmental sources of VCO1 were characterized, whole-genome sequenced and compared to globally available seventh pandemic (7P) strains of V. cholerae at SNP resolution. Final analyses included 636 isolates. Novel Ghanaian isolates clustered into three distinct clades (clades 1, 2 and 3) in wave 3 of the 7P lineage. The closest relatives of our novel Ghanaian isolates were from Benin, Cameroon, Togo, Niger and Nigeria. All novel Ghanaian isolates were multi-drug resistant. Environmental isolates clustered into clade 2, despite being isolated years later, showing the possibility of persistence and re-emergence of older clades. A lag phase of several years from estimated introduction to reported cases suggests pathogen persistence in the absence of reported cholera cases. These results highlight the importance of deeper surveillance for understanding transmission routes between bordering countries and planning tailored vaccination campaigns in an effort to eradicate cholera.

Enteric fever infections remain a significant public health issue, with up to 20 million infections per year. Increasing rates of antibiotic resistant strains have rendered many first-line antibiotics potentially ineffective. Genotype 4.3.1 (H58) is the main circulating lineage of S. Typhi in many South Asian countries and is associated with high levels of antibiotic resistance. The emergence and spread of extensively drug resistant (XDR) typhoid strains has increased the need for a rapid molecular test to identify and track these high-risk lineages for surveillance and vaccine prioritisation. Current methods require samples to be cultured for several days, followed by DNA extraction and sequencing to determine the specific lineage. We designed and evaluated the performance of a new multiplex PCR assay, targeting S. Paratyphi A as well as the H58 and XDR lineages of S. Typhi on a collection of bacterial strains. Our assay was 100% specific for the identification of lineage specific S. Typhi and S. Paratyphi A, when tested with a mix of non-Typhi Salmonella and non-Salmonella strains. With additional testing on clinical and environmental samples, this assay will allow rapid lineage level detection of typhoid of clinical significance, at a significantly lower cost to whole-genome sequencing. To our knowledge, this is the first report of a SNP-based multiplex PCR assay for the detection of lineage specific serovars of Salmonella Typhi.Data StatementAll supporting data, code and protocols have been provided within the article or through supplementary data files.

The emergence of increasingly antimicrobial-resistant (AMR) Salmonella enterica serovar Typhi (S. Typhi) threatens to undermine effective treatment and control. Here, aiming to investigate the temporal and geographic patterns of emergence and spread of AMR S. Typhi, we sequenced 3,489 S. Typhi isolated from prospective surveillance in South Asia and combined these with a global collection of 4,169 S. Typhi genomes. Our analysis revealed that independent acquisition of plasmids and homoplastic mutations conferring AMR have occurred repeatedly in multiple lineages of S. Typhi, predominantly arising in South Asia. We found evidence of frequent international and intercontinental transfers of AMR S. Typhi, followed by rapid expansion and replacement of antimicrobial-susceptible clades.

Microbes evolve rapidly by modifying their genome through mutations or acquisition of genetic elements. Antimicrobial resistance in Helicobacter pylori is increasingly prevalent in India. However, limited information is available about the genome of resistant H. pylori isolated from India. Our pan- and core-genome based analyses of 54 Indian H. pylori strains revealed plasticity of its genome. H. pylori is highly heterogenous both in terms of the genomic content and DNA sequence homology of ARGs and virulence factors. We observed that the H. pylori strains are clustered according to their geographical locations. The presence of point mutations in the ARGs and absence of acquired genetic elements linked with ARGs suggest target modifications are the primary mechanism of its antibiotic resistance. The findings of the present study would help in better understanding the emergence of drug-resistant H. pylori and controlling gastric disorders by advancing clinical guidance on selected treatment regimens.

Diphtheria is a respiratory disease caused by the bacterium Corynebacterium diphtheriae. Although the development of a toxin-based vaccine in the 1930s has allowed a high level of control over the disease, cases have increased in recent years. Here, we describe the genomic variation of 502 C. diphtheriae isolates across 16 countries and territories over 122 years. We generate a core gene phylogeny and determine the presence of antimicrobial resistance genes and variation within the tox gene of 291 tox+ isolates. Numerous, highly diverse clusters of C. diphtheriae are observed across the phylogeny, each containing isolates from multiple countries, regions and time of isolation. The number of antimicrobial resistance genes, as well as the breadth of antibiotic resistance, is substantially greater in the last decade than ever before. We identified and analysed 18 tox gene variants, with mutations estimated to be of medium to high structural impact., Cases of diphtheria have increased in recent years. Here, the authors analyse the genomes of 502 Corynebacterium diphtheriae isolates across 16 countries and territories over 122 years, describing an increase in antimicrobial resistance genes and identifying toxin variants.

The currently ongoing COVID-19 pandemic caused by SARS-CoV-2 has accounted for millions of infections and deaths across the globe. Genome sequences of SARS-CoV-2 are being published daily in public databases and the availability of this genome datasets has allowed unprecedented access into the mutational patterns of SARS-CoV-2 evolution. We made use of the same genomic information for conducting phylogenetic analysis and identifying lineage-specific mutations. The catalogued lineage defining mutations were analysed for their stabilizing or destabilizing impact on viral proteins. We recorded persistence of D614G, S477N, A222V V1176F variants and a global expansion of the PANGOLIN variant B.1. In addition, a retention of Q57H (B.1.X), R203K/G204R (B.1.1.X), T85I (B.1.2-B.1.3), G15S+T428I (C.X) and I120F (D.X) variations was observed. Overall, we recorded a striking balance between stabilizing and destabilizing mutations, therefore well-maintained protein structures. With selection pressures in the form of newly developed vaccines and therapeutics to mount soon in coming months, the task of mapping of viral mutations and recording of their impact on key viral proteins would be crucial to pre-emptively catch any escape mechanism that SARS-CoV-2 may evolve for.STUDY IMPORTANCEAs large numbers of the SARS CoV-2 genome sequences are shared in publicly accessible repositories, it enables scientists a detailed evolutionary analysis since its initial isolation in Wuhan, China. We investigated the evolutionarily associated mutational diversity overlaid on the major phylogenetic lineages circulating globally, using 513 representative genomes. We detailed phylogenetic persistence of key variants facilitating global expansion of the PANGOLIN variant B.1, including the recent, fast expanding, B.1.1.7 lineage. The stabilizing or destabilizing impact of the catalogued lineage defining mutations on viral proteins indicates their possible involvement in balancing the protein function and structure. A clear understanding of this mutational profile is of high clinical significance to catch any vaccine escape mechanism, as the same proteins make crucial components of vaccines recently approved and in development. In this direction, our study provides an imperative framework and baseline data upon which further analysis could be built as newer variants of SARS-CoV-2 continue to appear.

Background Typhoid fever caused by Salmonella Typhi is a major public health concern in low-/middle-income countries. A recent study of 1900 global S. Typhi indicated that South Asia might be the site of the original emergence of the most successful and hypervirulent clone belonging to the 4.3.1 genotype. However, this study had limited samples from India. Methods We analyzed 194 clinical S. Typhi, temporal representatives from those isolated from blood and bone marrow cultures in southern India, over 26 years (1991–2016). Antimicrobial resistance (AMR) testing was performed for most common clinical agents. Whole-genome sequencing and SNP-level analysis was conducted. Comparative genomics of Vellore isolates was performed to infer transmission and AMR events. Results We identified multidrug-resistance (MDR)–associated clade 4.3.1 as the dominant genotype. We detected 4.3.1 S. Typhi as early as 1991, the earliest to be reported form India, and the majority were fluoroquinolone resistant and not MDR. MDR was not detected at all in other genotypes circulating in Vellore. Comparison with global S. Typhi showed 2 Vellore subgroups (I and II) that were phylogenetically highly related to previously described South Asia (subgroup I, II) and Southeast Asia (subgroup II) clades. Conclusions 4.3.1 S. Typhi has dominated in Vellore for 2 decades. Our study would assist public health agencies in better tracking of transmission and persistence of this successful clade in India and globally. It informs clinicians of the AMR pattern of circulating clone, which would add confidence to their prophylactic/treatment decision making and facilitate efficient patient care., The molecular epidemiology of Salmonella Typhi circulating in India since early 1990s and its dominance is reported. An in-depth AMR profiling of the major drug-resistant lineage, 4.3.1, would help in management and for public health agencies in planning intervention strategies.

BackgroundRecent 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.MethodsFive 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.ResultsComparative genomic analysis and detailed plasmid characterization indicate that while in Pakistan (4.3.1 lineage I) the XDR trait is associated with blaCTX-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.ConclusionSince 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.ImportanceGenomic 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.

Shigella is the second leading cause of bacterial diarrhea worldwide. Recently, Shigella sonnei seems to be replacing Shigella flexneri in low- and middle-income countries undergoing economic development. Despite this, studies focusing on these species at the genomic level remain largely unexplored. Here, we compared the genome sequences of S. flexneri and S. sonnei isolates from India with the publicly available genomes of global strains. Our analysis provides evidence for the long-term persistence of all phylogenetic groups (PGs) of S. flexneri and the recent dominance of the ciprofloxacin-resistant S. sonnei lineage in India. Within S. flexneri PGs, the majority of the study isolates belonged to PG3 within the predominance of serotype 2. For S. sonnei, the current pandemic involves globally distributed multidrug-resistant (MDR) clones that belong to Central Asia lineage III. The presence of such epidemiologically dominant lineages in association with stable antimicrobial resistance (AMR) determinants results in successful survival in the community. IMPORTANCE Shigella is the second leading cause of bacterial diarrhea worldwide. This has been categorized as a priority pathogen among enteric bacteria by the Global Antimicrobial Resistance Surveillance System (GLASS) of the World Health Organization (WHO). Recently, S. sonnei seems to be replacing S. flexneri in low- and middle-income countries undergoing economic development. Antimicrobial resistance in S. flexneri and S. sonnei is a growing international concern, specifically with the international dominance of the multidrug-resistant (MDR) lineage. Genomic studies focusing on S. flexneri and S. sonnei in India remain largely unexplored. This study provides information on the introduction and expansion of drug-resistant Shigella strains in India for the first time by comparing the genome sequences of S. flexneri and S. sonnei isolates from India with the publicly available genomes of global strains. The study discusses the key differences between the two dominant species of Shigella at the genomic level to understand the evolutionary trends and genome dynamics of emerging and existing resistance clones. The present work demonstrates evidence for the long-term persistence of all PGs of S. flexneri and the recent dominance of a ciprofloxacin-resistant S. sonnei lineage in India.

Shigella is the second leading cause of bacterial diarrhea worldwide. This has been categorized as a priority pathogen among enteric bacteria by the Global Antimicrobial Resistance Surveillance System (GLASS) of the World Health Organization (WHO). Recently, S. sonnei seems to be replacing S. flexneri in low- and middle-income countries undergoing economic development. Antimicrobial resistance in S. flexneri and S. sonnei is a growing international concern, specifically with the international dominance of the multidrug-resistant (MDR) lineage. Genomic studies focusing on S. flexneri and S. sonnei in India remain largely unexplored. This study provides information on the introduction and expansion of drug-resistant Shigella strains in India for the first time by comparing the genome sequences of S. flexneri and S. sonnei isolates from India with the publicly available genomes of global strains. The study discusses the key differences between the two dominant species of Shigella at the genomic level to understand the evolutionary trends and genome dynamics of emerging and existing resistance clones. The present work demonstrates evidence for the long-term persistence of all PGs of S. flexneri and the recent dominance of a ciprofloxacin-resistant S. sonnei lineage in India., Shigella is the second leading cause of bacterial diarrhea worldwide. Recently, Shigella sonnei seems to be replacing Shigella flexneri in low- and middle-income countries undergoing economic development. Despite this, studies focusing on these species at the genomic level remain largely unexplored. Here, we compared the genome sequences of S. flexneri and S. sonnei isolates from India with the publicly available genomes of global strains. Our analysis provides evidence for the long-term persistence of all phylogenetic groups (PGs) of S. flexneri and the recent dominance of the ciprofloxacin-resistant S. sonnei lineage in India. Within S. flexneri PGs, the majority of the study isolates belonged to PG3 within the predominance of serotype 2. For S. sonnei, the current pandemic involves globally distributed multidrug-resistant (MDR) clones that belong to Central Asia lineage III. The presence of such epidemiologically dominant lineages in association with stable antimicrobial resistance (AMR) determinants results in successful survival in the community. IMPORTANCE Shigella is the second leading cause of bacterial diarrhea worldwide. This has been categorized as a priority pathogen among enteric bacteria by the Global Antimicrobial Resistance Surveillance System (GLASS) of the World Health Organization (WHO). Recently, S. sonnei seems to be replacing S. flexneri in low- and middle-income countries undergoing economic development. Antimicrobial resistance in S. flexneri and S. sonnei is a growing international concern, specifically with the international dominance of the multidrug-resistant (MDR) lineage. Genomic studies focusing on S. flexneri and S. sonnei in India remain largely unexplored. This study provides information on the introduction and expansion of drug-resistant Shigella strains in India for the first time by comparing the genome sequences of S. flexneri and S. sonnei isolates from India with the publicly available genomes of global strains. The study discusses the key differences between the two dominant species of Shigella at the genomic level to understand the evolutionary trends and genome dynamics of emerging and existing resistance clones. The present work demonstrates evidence for the long-term persistence of all PGs of S. flexneri and the recent dominance of a ciprofloxacin-resistant S. sonnei lineage in India.

Background\ud Multidrug-resistant (MDR) E. coli with extended-spectrum β-lactamases (ESBLs) is becoming endemic in health care settings around the world. Baseline data on virulence and antimicrobial resistance (AMR) of specific lineages of E. coli circulating in developing countries like India is currently lacking.\ud \ud Methods\ud Whole-genome sequencing was performed for 60 MDR E. coli isolates. The analysis was performed at single nucleotide polymorphism (SNP) level resolution to identify the presence of their virulence and AMR genes.\ud \ud Results\ud Genome comparison revealed the presence of ST-131 global MDR and ST410 as emerging-MDR clades of E. coli in India. AMR gene profile for cephalosporin and carbapenem resistance differed between the clades. Genotypes blaCTX-M-15 and blaNDM-5 were common among cephalosporinases and carbapenemases, respectively. For aminoglycoside resistance, rmtB was positive for 31.7% of the isolates, of which 95% were co-harboring carbapenemases. In addition, the FimH types and virulence gene profile positively correlated with the SNP based phylogeny, and also revealed the evolution of MDR clones among the study population with temporal accumulation of SNPs. The predominant clone was ST167 (blaNDM lineage) followed by ST405 (global clone ST131 equivalent) and ST410 (fast spreading high risk clone).\ud \ud Conclusions\ud This is the first report on the whole genome analysis of MDR E. coli lineages circulating in India. Data from this study will provide public health agencies with baseline information on AMR and virulent genes in pathogenic E. coli in the region.

Antimicrobial resistance (AMR), from a microbial evolution perspective, is a survival response. Evolution is generally a natural phenomenon occurring over the course of several millennia. However, the discrepancy in the rate of evolution and adaptation driven by antimicrobials is remarkably striking. AMR has progressed rapidly from the very first recorded case of penicillin resistance in the early 1940s to the widespread global public health threat it poses today. With very limited new treatment options currently in the pipeline, the increasing trend of AMR is likely to leave the human population highly vulnerable to easily treatable infections in the near future.

Diphtheria is a potentially fatal infection mostly caused by toxigenic Corynebacterium diphtheriae strains and occasionally by toxigenic C. ulcerans and C. pseudotuberculosis strains. Diphtheria is generally an acute respiratory infection, characterized by the formation of a pseudomembrane in the throat, but cutaneous infections are possible. Systemic effects, such as myocarditis and neuropathy, which are associated with increased fatality risk, are due to diphtheria toxin, an exotoxin produced by the pathogen that inhibits protein synthesis and causes cell death. Clinical diagnosis is confirmed by the isolation and identification of the causative Corynebacterium spp., usually by bacterial culture followed by enzymatic and toxin detection tests. Diphtheria can be treated with the timely administration of diphtheria antitoxin and antimicrobial therapy. Although effective vaccines are available, this disease has the potential to re-emerge in countries where the recommended vaccination programmes are not sustained, and increasing proportions of adults are becoming susceptible to diphtheria. Thousands of diphtheria cases are still reported annually from several countries in Asia and Africa, along with many outbreaks. Changes in the epidemiology of diphtheria have been reported worldwide. The prevalence of toxigenic Corynebacterium spp. highlights the need for proper clinical and epidemiological investigations to quickly identify and treat affected individuals, along with public health measures to prevent and contain the spread of this disease.