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1.
Nature ; 611(7934): 167-172, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36261522

RESUMEN

Most membrane proteins are synthesized on endoplasmic reticulum (ER)-bound ribosomes docked at the translocon, a heterogeneous ensemble of transmembrane factors operating on the nascent chain1,2. How the translocon coordinates the actions of these factors to accommodate its different substrates is not well understood. Here we define the composition, function and assembly of a translocon specialized for multipass membrane protein biogenesis3. This 'multipass translocon' is distinguished by three components that selectively bind the ribosome-Sec61 complex during multipass protein synthesis: the GET- and EMC-like (GEL), protein associated with translocon (PAT) and back of Sec61 (BOS) complexes. Analysis of insertion intermediates reveals how features of the nascent chain trigger multipass translocon assembly. Reconstitution studies demonstrate a role for multipass translocon components in protein topogenesis, and cells lacking these components show reduced multipass protein stability. These results establish the mechanism by which nascent multipass proteins selectively recruit the multipass translocon to facilitate their biogenesis. More broadly, they define the ER translocon as a dynamic assembly whose subunit composition adjusts co-translationally to accommodate the biosynthetic needs of its diverse range of substrates.


Asunto(s)
Proteínas de la Membrana , Retículo Endoplásmico/metabolismo , Proteínas de la Membrana/metabolismo , Transporte de Proteínas , Ribosomas/metabolismo , Canales de Translocación SEC/metabolismo , Especificidad por Sustrato , Estabilidad Proteica
2.
J Biol Chem ; 297(3): 101046, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34358566

RESUMEN

Bacteria require high-efficiency uptake systems to survive and proliferate in nutrient-limiting environments, such as those found in host organisms. ABC transporters in the bacterial plasma membrane provide a mechanism for transport of many substrates. In this study, we examine an operon containing a periplasmic binding protein in Actinobacillus for its potential role in nutrient acquisition. The electron density map of 1.76 Å resolution obtained from the crystal structure of the periplasmic binding protein was best fit with a molecular model containing a pyridoxal-5'-phosphate (P5P/pyridoxal phosphate/the active form of vitamin B6) ligand within the protein's binding site. The identity of the P5P bound to this periplasmic binding protein was verified by isothermal titration calorimetry, microscale thermophoresis, and mass spectrometry, leading us to name the protein P5PA and the operon P5PAB. To illustrate the functional utility of this uptake system, we introduced the P5PAB operon from Actinobacillus pleuropneumoniae into an Escherichia coli K-12 strain that was devoid of a key enzyme required for P5P synthesis. The growth of this strain at low levels of P5P supports the functional role of this operon in P5P uptake. This is the first report of a dedicated P5P bacterial uptake system, but through bioinformatics, we discovered homologs mainly within pathogenic representatives of the Pasteurellaceae family, suggesting that this operon exists more widely outside the Actinobacillus genus.


Asunto(s)
Transportadoras de Casetes de Unión a ATP/metabolismo , Actinobacillus pleuropneumoniae/metabolismo , Proteínas Bacterianas/metabolismo , Vitamina B 6/metabolismo , Transportadoras de Casetes de Unión a ATP/química , Transportadoras de Casetes de Unión a ATP/genética , Actinobacillus pleuropneumoniae/química , Actinobacillus pleuropneumoniae/genética , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Sitios de Unión , Transporte Biológico , Escherichia coli/genética , Escherichia coli/metabolismo , Modelos Moleculares , Operón , Proteínas de Unión Periplasmáticas/química , Proteínas de Unión Periplasmáticas/genética , Proteínas de Unión Periplasmáticas/metabolismo , Fosfato de Piridoxal/química , Fosfato de Piridoxal/metabolismo , Vitamina B 6/química
3.
Mol Syst Biol ; 16(12): e9310, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33438817

RESUMEN

Many proteins involved in signal transduction contain peptide recognition modules (PRMs) that recognize short linear motifs (SLiMs) within their interaction partners. Here, we used large-scale peptide-phage display methods to derive optimal ligands for 163 unique PRMs representing 79 distinct structural families. We combined the new data with previous data that we collected for the large SH3, PDZ, and WW domain families to assemble a database containing 7,984 unique peptide ligands for 500 PRMs representing 82 structural families. For 74 PRMs, we acquired enough new data to map the specificity profiles in detail and derived position weight matrices and binding specificity logos based on multiple peptide ligands. These analyses showed that optimal peptide ligands resembled peptides observed in existing structures of PRM-ligand complexes, indicating that a large majority of the phage-derived peptides are likely to target natural peptide-binding sites and could thus act as inhibitors of natural protein-protein interactions. The complete dataset has been assembled in an online database (http://www.prm-db.org) that will enable many structural, functional, and biological studies of PRMs and SLiMs.


Asunto(s)
Bases de Datos de Proteínas , Péptidos/metabolismo , Encuestas y Cuestionarios , Secuencia de Aminoácidos , Bacteriófagos/metabolismo , Humanos , Ligandos , Péptidos/química
4.
Clin Infect Dis ; 68(Suppl 2): S117-S123, 2019 03 07.
Artículo en Inglés | MEDLINE | ID: mdl-30845325

RESUMEN

BACKGROUND: Typhoid and paratyphoid remain the most common bloodstream infections in many resource-poor settings. The World Health Organization recommends typhoid conjugate vaccines for country-specific introduction, but questions regarding typhoid and paratyphoid epidemiology persist, especially regarding their severity in young children. METHODS: We conducted enteric fever surveillance in Bangladesh from 2004 through 2016 in the inpatient departments of 2 pediatric hospitals and the outpatient departments of 1 pediatric hospital and 1 private consultation clinic. Blood cultures were conducted at the discretion of the treating physicians; cases of culture-confirmed typhoid/paratyphoid were included. Hospitalizations and durations of hospitalizations were used as proxies for severity in children <12 years old. RESULTS: We identified 7072 typhoid and 1810 paratyphoid culture-confirmed cases. There was no increasing trend in the proportion of paratyphoid over the 13 years. The median age in the typhoid cases was 60 months, and 15% of the cases occurred in children <24 months old. The median age of the paratyphoid cases was significantly higher, at 90 months (P < .001); 9.4% were in children <24 months old. The proportion of children (<12 years old) hospitalized with typhoid and paratyphoid (32% and 21%, respectively) decreased with age; there was no significant difference in durations of hospitalizations between age groups. However, children with typhoid were hospitalized for longer than those with paratyphoid. CONCLUSIONS: Typhoid and paratyphoid fever are common in Dhaka, including among children under 2 years old, who have equivalent disease severity as older children. Early immunization with typhoid conjugate vaccines could avert substantial morbidity, but broader efforts are required to reduce the paratyphoid burden.


Asunto(s)
Monitoreo Epidemiológico , Fiebre Paratifoidea/epidemiología , Fiebre Tifoidea/epidemiología , Vacunación/legislación & jurisprudencia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Bangladesh/epidemiología , Niño , Preescolar , Hospitalización/estadística & datos numéricos , Humanos , Lactante , Recién Nacido , Persona de Mediana Edad , Fiebre Paratifoidea/diagnóstico , Fiebre Paratifoidea/prevención & control , Índice de Severidad de la Enfermedad , Vacunas Tifoides-Paratifoides/administración & dosificación , Adulto Joven
5.
PLoS Pathog ; 11(8): e1005107, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26295949

RESUMEN

Efficient acquisition of extracellular nutrients is essential for bacterial pathogenesis, however the identities and mechanisms for transport of many of these substrates remain unclear. Here, we investigate the predicted iron-binding transporter AfuABC and its role in bacterial pathogenesis in vivo. By crystallographic, biophysical and in vivo approaches, we show that AfuABC is in fact a cyclic hexose/heptose-phosphate transporter with high selectivity and specificity for a set of ubiquitous metabolites (glucose-6-phosphate, fructose-6-phosphate and sedoheptulose-7-phosphate). AfuABC is conserved across a wide range of bacterial genera, including the enteric pathogens EHEC O157:H7 and its murine-specific relative Citrobacter rodentium, where it lies adjacent to genes implicated in sugar sensing and acquisition. C. rodentium ΔafuA was significantly impaired in an in vivo murine competitive assay as well as its ability to transmit infection from an afflicted to a naïve murine host. Sugar-phosphates were present in normal and infected intestinal mucus and stool samples, indicating that these metabolites are available within the intestinal lumen for enteric bacteria to import during infection. Our study shows that AfuABC-dependent uptake of sugar-phosphates plays a critical role during enteric bacterial infection and uncovers previously unrecognized roles for these metabolites as important contributors to successful pathogenesis.


Asunto(s)
Metabolismo de los Hidratos de Carbono/fisiología , Infecciones por Enterobacteriaceae/metabolismo , Infecciones por Enterobacteriaceae/transmisión , Intestinos/microbiología , Animales , Transporte Biológico Activo/fisiología , Calorimetría , Cromatografía Liquida , Citrobacter rodentium , Mucosa Intestinal/metabolismo , Ratones , Ratones Endogámicos C57BL , Microscopía Fluorescente , Mutagénesis Sitio-Dirigida , Fosforilación , Filogenia , Espectrometría de Masas en Tándem
6.
Lancet Digit Health ; 6(7): e520-e525, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38906617

RESUMEN

Historical legacies of colonialism affect the distribution and control of scientific knowledge today, including within the pathogen genomics field, which remains dominated by high-income countries (HICs). We discuss the imperatives for decolonising pathogen genomics, including the need for more equitable representation, collaboration, and capacity-strengthening, and the shared responsibilities that both low-income and middle-income countries (LMICs) and HICs have in this endeavour. By highlighting examples from LMICs, we illuminate the pathways and challenges that researchers in LMICs face in the bid to gain autonomy in this crucial domain. Recognising the inherent value of local expertise and resources, we argue for a more inclusive, globally collaborative approach to pathogen genomics. Such an approach not only fosters scientific growth and innovation, but also strengthens global health security by equipping all nations with the tools needed to respond to health crises.


Asunto(s)
Colonialismo , Países en Desarrollo , Genómica , Humanos , Salud Global
7.
PLoS Negl Trop Dis ; 18(2): e0011822, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38358956

RESUMEN

Typhoid-conjugate vaccines (TCVs) provide an opportunity to reduce the burden of typhoid fever, caused by Salmonella Typhi, in endemic areas. As policymakers design vaccination strategies, accurate and high-resolution data on disease burden is crucial. However, traditional blood culture-based surveillance is resource-extensive, prohibiting its large-scale and sustainable implementation. Salmonella Typhi is a water-borne pathogen, and here, we tested the potential of Typhi-specific bacteriophage surveillance in surface water bodies as a low-cost tool to identify where Salmonella Typhi circulates in the environment. In 2021, water samples were collected and tested for the presence of Salmonella Typhi bacteriophages at two sites in Bangladesh: urban capital city, Dhaka, and a rural district, Mirzapur. Salmonella Typhi-specific bacteriophages were detected in 66 of 211 (31%) environmental samples in Dhaka, in comparison to 3 of 92 (3%) environmental samples from Mirzapur. In the same year, 4,620 blood cultures at the two largest pediatric hospitals of Dhaka yielded 215 (5%) culture-confirmed typhoid cases, and 3,788 blood cultures in the largest hospital of Mirzapur yielded 2 (0.05%) cases. 75% (52/69) of positive phage samples were collected from sewage. All isolated phages were tested against a panel of isolates from different Salmonella Typhi genotypes circulating in Bangladesh and were found to exhibit a diverse killing spectrum, indicating that diverse bacteriophages were isolated. These results suggest an association between the presence of Typhi-specific phages in the environment and the burden of typhoid fever, and the potential of utilizing environmental phage surveillance as a low-cost tool to assist policy decisions on typhoid control.


Asunto(s)
Bacteriófagos , Fiebre Tifoidea , Vacunas Tifoides-Paratifoides , Humanos , Niño , Fiebre Tifoidea/epidemiología , Fiebre Tifoidea/prevención & control , Bangladesh/epidemiología , Salmonella typhi/genética , Agua
8.
Vaccine ; 42(11): 2867-2876, 2024 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-38531727

RESUMEN

PURPOSE: Typhoid fever causes substantial morbidity and mortality in Bangladesh. The government of Bangladesh plans to introduce typhoid conjugate vaccines (TCV) in its expanded program on immunization (EPI) schedule. However, the optimal introduction strategy in addition to the costs and benefits of such a program are unclear. METHODS: We extended an existing mathematical model of typhoid transmission to integrate cost data, clinical incidence data, and recently conducted serosurveys in urban, semi-urban, and rural areas. In our primary analysis, we evaluated the status quo (i.e., no vaccination) and eight vaccine introduction strategies including routine and 1-time campaign strategies, which differed by age groups targeted and geographic focus. Model outcomes included clinical incidence, seroincidence, deaths, costs, disability-adjusted life years (DALYs), and incremental cost-effectiveness ratios (ICERs) for each strategy. We adopted a societal perspective, 10-year model time horizon, and 3 % annual discount rate. We performed probabilistic, one-way, and scenario sensitivity analyses including adopting a healthcare perspective and alternate model time horizons. RESULTS: We projected that all TCV strategies would be cost saving compared to the status quo. The preferred strategy was a nationwide introduction of TCV at 9-12 months of age with a single catch-up campaign for children ages 1-15, which was cost saving compared to all other strategies and the status quo. In the 10 years following implementation, we projected this strategy would avert 3.77 million cases (95 % CrI: 2.60 - 5.18), 11.31 thousand deaths (95 % CrI: 3.77 - 23.60), and save $172.35 million (95 % CrI: -14.29 - 460.59) compared to the status quo. Our findings were broadly robust to changes in parameter values and willingness-to-pay thresholds. CONCLUSIONS: We projected that nationwide TCV introduction with a catch-up campaign would substantially reduce typhoid incidence and very likely be cost saving in Bangladesh.


Asunto(s)
Fiebre Tifoidea , Vacunas Tifoides-Paratifoides , Niño , Humanos , Fiebre Tifoidea/epidemiología , Fiebre Tifoidea/prevención & control , Análisis Costo-Beneficio , Vacunas Conjugadas , Salud Pública , Bangladesh/epidemiología
9.
Vaccine ; 42(2): 255-262, 2024 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-38071104

RESUMEN

The 10-valent pneumococcal conjugate vaccine (PCV10) was introduced in March 2015 in Bangladesh. In this study, we aimed to estimate the impact of PCV10 on invasive pneumococcal disease (IPD) identified by blood cultures and severe pneumonia identified clinically and its effectiveness on invasive disease caused by vaccine serotypes. We conducted population-based surveillance among children aged 2- <24 months between April 2012 through March 2019 in Mirzapur, a rural sub-district of Bangladesh. We compared incidence of IPD and severe pneumonia before (April 2012 to March 2015) and after (April 2015 to March 2019) the introduction of PCV10. Vaccine effectiveness was measured using an indirect cohort analysis of data from four sentinel sites in which PCV10 vaccination status was compared between children with IPD caused by vaccine serotype vs. non-vaccine serotypes. We identified 24 IPD cases by blood culture and 1,704 severe pneumonia hospitalizations during the surveillance period. IPD incidence in under-2-year-old children fell 25 % (95 % CI: -1.2 % to 76 %; p-value = 0.59) from 106 cases per 100,000 child-years at baseline to 79.3 in April 2018- March 2019. Vaccine serotype-IPD incidence was lower (77 % reduction, 95 % CI: -0.45 % to 96 %; p-value = 0.068) in April 2018 - March 2019 than in the pre-vaccine period (85.7 cases to 19.8/100,000 child-years). A significant decline of 54.0 % (95 % CI: 47.0 % to 59.0 %; p-value < 0.001) was observed in hospitalizations due to severe pneumonia. From indirect cohort analysis, the effectiveness of PCV10 against vaccine serotype IPD was 37 % (95 % CI: -141.0 % to 83.5 %; p = 0.5) after the 1st dose and 63.1 % (95 % CI: -3.3 % to 85.9 %, p = 0.0411) after the 2nd or the 3rd dose. This study demonstrates that PCV10 introduction prevented hospitalizations with severe pneumonia and provided individual protection against vaccine serotypes.


Asunto(s)
Infecciones Neumocócicas , Neumonía , Humanos , Lactante , Preescolar , Vacunas Conjugadas/uso terapéutico , Estudios Prospectivos , Bangladesh/epidemiología , Infecciones Neumocócicas/epidemiología , Infecciones Neumocócicas/prevención & control , Vacunas Neumococicas/uso terapéutico , Incidencia , Serogrupo
10.
Open Forum Infect Dis ; 10(Suppl 1): S53-S57, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-37274527

RESUMEN

Salmonella enterica serovar Paratyphi A, the causative agent of paratyphoid fever, is a neglected tropical disease with a high burden and mortality in low- and middle-income countries. Limited information is available regarding its genomic diversity, especially from South Asian countries that are collectively responsible for >80% of all paratyphoid cases. At the 2021 International Conference on Typhoid and Other Salmonelloses, researchers from the around the globe presented their work on Salmonella Paratyphi A genomics. Presentations described recent genomic data from South Asia and the development of Paratype, an open-access single-nucleotide polymorphism-based genotyping scheme, to segregate Salmonella Paratyphi A genomes in a systematic and sustainable manner. In this review, we attempt to summarize the progress made thus far on Salmonella Paratyphi A genomics and discuss the questions that remain to better understand the pathogen and develop interventions to fight it.

11.
PLoS Negl Trop Dis ; 17(11): e0011723, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37939101

RESUMEN

BACKGROUND: Typhoid and paratyphoid remain common bloodstream infections in areas with suboptimal water and sanitation infrastructure. Paratyphoid, caused by Salmonella Paratyphi A, is less prevalent than typhoid and its antimicrobial resistance (AMR) trends are less documented. Empirical treatment for paratyphoid is commonly based on the knowledge of susceptibility of Salmonella Typhi, which causes typhoid. Hence, with rising drug resistance in Salmonella Typhi, last-line antibiotics like ceftriaxone and azithromycin are prescribed for both typhoid and paratyphoid. However, unlike for typhoid, there is no vaccine to prevent paratyphoid. Here, we report 23-year AMR trends of Salmonella Paratyphi A in Bangladesh. METHODS: From 1999 to 2021, we conducted enteric fever surveillance in two major pediatric hospitals and three clinics in Dhaka, Bangladesh. Blood cultures were performed at the discretion of the treating physicians; cases were confirmed by culture, serological and biochemical tests. Antimicrobial susceptibility was determined following CLSI guidelines. RESULTS: Over 23 years, we identified 2,725 blood culture-confirmed paratyphoid cases. Over 97% of the isolates were susceptible to ampicillin, chloramphenicol, and cotrimoxazole, and no isolate was resistant to all three. No resistance to ceftriaxone was recorded, and >99% of the isolates were sensitive to azithromycin. A slight increase in minimum inhibitory concentration (MIC) is noticed for ceftriaxone but the current average MIC is 32-fold lower than the resistance cut-off. Over 99% of the isolates exhibited decreased susceptibility to ciprofloxacin. CONCLUSIONS: Salmonella Paratyphi A has remained susceptible to most antibiotics, unlike Salmonella Typhi, despite widespread usage of many antibiotics in Bangladesh. The data can guide evidence-based policy decisions for empirical treatment of paratyphoid fever, especially in the post typhoid vaccine era, and with the availability of new paratyphoid diagnostics.


Asunto(s)
Fiebre Paratifoidea , Fiebre Tifoidea , Niño , Humanos , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Fiebre Tifoidea/epidemiología , Fiebre Tifoidea/tratamiento farmacológico , Salmonella paratyphi A , Azitromicina/farmacología , Azitromicina/uso terapéutico , Ceftriaxona/farmacología , Bangladesh/epidemiología , Farmacorresistencia Bacteriana , Salmonella typhi , Fiebre Paratifoidea/epidemiología , Pruebas de Sensibilidad Microbiana
12.
Elife ; 122023 09 12.
Artículo en Inglés | MEDLINE | ID: mdl-37697804

RESUMEN

Background: The Global Typhoid Genomics Consortium was established to bring together the typhoid research community to aggregate and analyse Salmonella enterica serovar Typhi (Typhi) genomic data to inform public health action. This analysis, which marks 22 years since the publication of the first Typhi genome, represents the largest Typhi genome sequence collection to date (n=13,000). Methods: This is a meta-analysis of global genotype and antimicrobial resistance (AMR) determinants extracted from previously sequenced genome data and analysed using consistent methods implemented in open analysis platforms GenoTyphi and Pathogenwatch. Results: Compared with previous global snapshots, the data highlight that genotype 4.3.1 (H58) has not spread beyond Asia and Eastern/Southern Africa; in other regions, distinct genotypes dominate and have independently evolved AMR. Data gaps remain in many parts of the world, and we show the potential of travel-associated sequences to provide informal 'sentinel' surveillance for such locations. The data indicate that ciprofloxacin non-susceptibility (>1 resistance determinant) is widespread across geographies and genotypes, with high-level ciprofloxacin resistance (≥3 determinants) reaching 20% prevalence in South Asia. Extensively drug-resistant (XDR) typhoid has become dominant in Pakistan (70% in 2020) but has not yet become established elsewhere. Ceftriaxone resistance has emerged in eight non-XDR genotypes, including a ciprofloxacin-resistant lineage (4.3.1.2.1) in India. Azithromycin resistance mutations were detected at low prevalence in South Asia, including in two common ciprofloxacin-resistant genotypes. Conclusions: The consortium's aim is to encourage continued data sharing and collaboration to monitor the emergence and global spread of AMR Typhi, and to inform decision-making around the introduction of typhoid conjugate vaccines (TCVs) and other prevention and control strategies. Funding: No specific funding was awarded for this meta-analysis. Coordinators were supported by fellowships from the European Union (ZAD received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 845681), the Wellcome Trust (SB, Wellcome Trust Senior Fellowship), and the National Health and Medical Research Council (DJI is supported by an NHMRC Investigator Grant [GNT1195210]).


Salmonella Typhi (Typhi) is a type of bacteria that causes typhoid fever. More than 110,000 people die from this disease each year, predominantly in areas of sub-Saharan Africa and South Asia with limited access to safe water and sanitation. Clinicians use antibiotics to treat typhoid fever, but scientists worry that the spread of antimicrobial-resistant Typhi could render the drugs ineffective, leading to increased typhoid fever mortality. The World Health Organization has prequalified two vaccines that are highly effective in preventing typhoid fever and may also help limit the emergence and spread of resistant Typhi. In low resource settings, public health officials must make difficult trade-off decisions about which new vaccines to introduce into already crowded immunization schedules. Understanding the local burden of antimicrobial-resistant Typhi and how it is spreading could help inform their actions. The Global Typhoid Genomics Consortium analyzed 13,000 Typhi genomes from 110 countries to provide a global overview of genetic diversity and antimicrobial-resistant patterns. The analysis showed great genetic diversity of the different strains between countries and regions. For example, the H58 Typhi variant, which is often drug-resistant, has spread rapidly through Asia and Eastern and Southern Africa, but is less common in other regions. However, distinct strains of other drug-resistant Typhi have emerged in other parts of the world. Resistance to the antibiotic ciprofloxacin was widespread and accounted for over 85% of cases in South Africa. Around 70% of Typhi from Pakistan were extensively drug-resistant in 2020, but these hard-to-treat variants have not yet become established elsewhere. Variants that are resistant to both ciprofloxacin and ceftriaxone have been identified, and azithromycin resistance has also appeared in several different variants across South Asia. The Consortium's analyses provide valuable insights into the global distribution and transmission patterns of drug-resistant Typhi. Limited genetic data were available fromseveral regions, but data from travel-associated cases helped fill some regional gaps. These findings may help serve as a starting point for collective sharing and analyses of genetic data to inform local public health action. Funders need to provide ongoing supportto help fill global surveillance data gaps.


Asunto(s)
Salmonella typhi , Fiebre Tifoidea , Humanos , Salmonella typhi/genética , Fiebre Tifoidea/epidemiología , Antibacterianos/farmacología , Viaje , Farmacorresistencia Bacteriana/genética , Ciprofloxacina
13.
Proteomics ; 12(10): 1697-705, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22593000

RESUMEN

Protein interactions have been at the focus of computational biology in recent years. In particular, interest has come from two different communities--structural and systems biology. Here, we will discuss key systems and structural biology methods that have been used for analysis and prediction of protein-protein interactions and the insight these approaches have provided on the nature and organization of protein-protein interactions inside cells.


Asunto(s)
Biología Computacional/métodos , Mapeo de Interacción de Proteínas/métodos , Proteínas/química , Proteínas/metabolismo , Animales , Inteligencia Artificial , Humanos , Ratones , Modelos Moleculares , Conformación Proteica , Mapas de Interacción de Proteínas
14.
Elife ; 112022 04 27.
Artículo en Inglés | MEDLINE | ID: mdl-35475756

RESUMEN

Surface lipoproteins (SLPs) are peripherally attached to the outer leaflet of the outer membrane in many Gram-negative bacteria, playing significant roles in nutrient acquisition and immune evasion in the host. While the factors that are involved in the synthesis and delivery of SLPs in the inner membrane are well characterized, the molecular machinery required for the movement of SLPs to the surface are still not fully elucidated. In this study, we investigated the translocation of a SLP TbpB through a Slam1-dependent pathway. Using purified components, we developed an in vitro translocation assay where unfolded TbpB is transported through Slam1-containing proteoliposomes, confirming Slam1 as an outer membrane translocon. While looking to identify factors to increase translocation efficiency, we discovered the periplasmic chaperone Skp interacted with TbpB in the periplasm of Escherichia coli. The presence of Skp was found to increase the translocation efficiency of TbpB in the reconstituted translocation assays. A knockout of Skp in Neisseria meningitidis revealed that Skp is essential for functional translocation of TbpB to the bacterial surface. Taken together, we propose a pathway for surface destined lipoproteins, where Skp acts as a holdase for Slam-mediated TbpB translocation across the outer membrane.


Asunto(s)
Proteínas de la Membrana Bacteriana Externa , Proteínas de Escherichia coli , Proteínas de la Membrana Bacteriana Externa/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Lipoproteínas/metabolismo , Periplasma/metabolismo
15.
Nat Commun ; 13(1): 7912, 2022 12 23.
Artículo en Inglés | MEDLINE | ID: mdl-36564386

RESUMEN

Salmonella Paratyphi A, the primary etiology of paratyphoid, is estimated to cause 3.4 million infections annually, worldwide. With rising antimicrobial resistance and no licensed vaccines, genomic surveillance is key to track and monitor transmission, but there is currently no reliable genotyping framework for this pathogen. Here, we sequence 817 isolates from South Asia and add 562 publicly available genomes to build a global database representing 37 countries, covering 1917-2019. We develop a single nucleotide polymorphism-based genotyping scheme, Paratype, that segregates Salmonella Paratyphi A population into three primary and nine secondary clades, and 18 genotypes. Each genotype is assigned a unique allele definition located on an essential gene. Using Paratype, we identify spatiotemporal genomic variation and antimicrobial resistance markers. We release Paratype as an open-access tool that can use raw read files from both Illumina and Nanopore platforms, and thus can assist surveillance studies tracking Salmonella Paratyphi A across the globe.


Asunto(s)
Antiinfecciosos , Fiebre Paratifoidea , Humanos , Salmonella paratyphi A/genética , Genotipo , Genómica
16.
Lancet Microbe ; 3(8): e567-e577, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35750070

RESUMEN

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Bill & Melinda Gates Foundation.


Asunto(s)
Antiinfecciosos , Quinolonas , Fiebre Tifoidea , Antibacterianos/farmacología , Antiinfecciosos/farmacología , Azitromicina/farmacología , Farmacorresistencia Bacteriana/genética , Fluoroquinolonas/farmacología , Genómica , Humanos , Estudios Prospectivos , Quinolonas/farmacología , Salmonella typhi/genética , Fiebre Tifoidea/tratamiento farmacológico
17.
Microbiol Resour Announc ; 10(1)2021 Jan 07.
Artículo en Inglés | MEDLINE | ID: mdl-33414342

RESUMEN

A nearly complete genome sequence of a dengue virus serotype 2 strain detected in the serum of a patient in 2019 during the largest outbreak of dengue fever in Bangladesh is reported.

18.
mBio ; 12(1)2021 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-33593966

RESUMEN

The rising prevalence of antimicrobial resistance in Salmonella enterica serovars Typhi and Paratyphi A, causative agents of typhoid and paratyphoid, have led to fears of untreatable infections. Of specific concern is the emerging resistance against azithromycin, the only remaining oral drug to treat extensively drug resistant (XDR) typhoid. Since the first report of azithromycin resistance from Bangladesh in 2019, cases have been reported from Nepal, India, and Pakistan. The genetic basis of this resistance is a single point mutation in the efflux pump AcrB (R717Q/L). Here, we report 38 additional cases of azithromycin-resistant (AzmR) Salmonella Typhi and Paratyphi A isolated in Bangladesh between 2016 and 2018. Using genomic analysis of 56 AzmR isolates from South Asia with AcrB-R717Q/L, we confirm that this mutation has spontaneously emerged in different Salmonella Typhi and Paratyphi A genotypes. The largest cluster of AzmR Typhi belonged to genotype 4.3.1.1; Bayesian analysis predicts the mutation to have emerged sometime in 2010. A travel-related Typhi isolate with AcrB-R717Q belonging to 4.3.1.1 was isolated in the United Kingdom, increasing fears of global spread. For real-time detection of AcrB-R717Q/L, we developed an extraction-free, rapid, and low-cost mismatch amplification mutation assay (MAMA). Validation of MAMA using 113 AzmR and non-AzmR isolates yielded >98% specificity and sensitivity versus phenotypic and whole-genome sequencing assays currently used for azithromycin resistance detection. With increasing azithromycin use, AcrB-R717Q/L is likely to be acquired by XDR strains. The proposed tool for active detection and surveillance of this mutation may detect pan-oral drug resistance early, giving us a window to intervene.IMPORTANCE In the early 1900s, with mortality of ∼30%, typhoid and paratyphoid ravaged parts of the world; with improved water, sanitation, and hygiene in resource-rich countries and the advent of antimicrobials, mortality dwindled to <1%. Today, the burden rests disproportionately on South Asia, where the primary means for combatting the disease is antimicrobials. However, prevalence of antimicrobial resistance is rising and, in 2016, an extensively drug resistant Typhi strain triggered an ongoing outbreak in Pakistan, leaving only one oral drug, azithromycin, to treat it. Since the description of emergence of azithromycin resistance, conferred by a point mutation in acrB (AcrB-R717Q/L) in 2019, there have been increasing numbers of reports. Using genomics and Bayesian analysis, we illustrate that this mutation emerged in approximately 2010 and has spontaneously arisen multiple times. Emergence of pan-oral drug resistant Salmonella Typhi is imminent. We developed a low-cost, rapid PCR tool to facilitate real-time detection and prevention policies.


Asunto(s)
Antibacterianos/farmacología , Azitromicina/farmacología , Farmacorresistencia Bacteriana/genética , Genotipo , Salmonella enterica/efectos de los fármacos , Salmonella enterica/genética , Salmonella typhi/efectos de los fármacos , Teorema de Bayes , Humanos , Pruebas de Sensibilidad Microbiana , Mutación Puntual , Salmonella typhi/clasificación , Salmonella typhi/genética , Secuenciación Completa del Genoma
19.
Nat Commun ; 12(1): 6270, 2021 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-34725337

RESUMEN

Nutrient acquisition systems are often crucial for pathogen growth and survival during infection, and represent attractive therapeutic targets. Here, we study the protein machinery required for heme uptake in the opportunistic pathogen Acinetobacter baumannii. We show that the hemO locus, which includes a gene encoding the heme-degrading enzyme, is required for high-affinity heme acquisition from hemoglobin and serum albumin. The hemO locus includes a gene coding for a heme scavenger (HphA), which is secreted by a Slam protein. Furthermore, heme uptake is dependent on a TonB-dependent receptor (HphR), which is important for survival and/or dissemination into the vasculature in a mouse model of pulmonary infection. Our results indicate that A. baumannii uses a two-component receptor system for the acquisition of heme from host heme reservoirs.


Asunto(s)
Infecciones por Acinetobacter/microbiología , Acinetobacter baumannii/metabolismo , Proteínas Bacterianas/metabolismo , Hemo/metabolismo , Acinetobacter baumannii/genética , Acinetobacter baumannii/crecimiento & desarrollo , Animales , Proteínas Bacterianas/genética , Transporte Biológico , Femenino , Humanos , Ratones Endogámicos BALB C , Familia de Multigenes
20.
Microbiol Resour Announc ; 9(24)2020 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-32527780

RESUMEN

The complete genome sequence of a novel coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) isolate obtained from a nasopharyngeal swab from a patient with COVID-19 in Bangladesh is reported.

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