Identification of potential new vaccine candidates in Salmonella typhi using reverse vaccinology and subtractive genomics-based approach

ABSTRACTSalmonella enterica serovar typhi is the causative agent of typhoid fever in human. The available vaccine lacks the effectiveness and further overuse of the antibiotics throughout the past decades lead to the emergence of antibiotic-resistant strains. To reduce the spread of antibiotic resistance, it is essential to develop new vaccines. In this study using an extensive bioinformatic analysis based on reverse vaccinology and subtractive genomics-based approach, we searched the genome of S typhi. We found that two outermost membrane proteins LptD and LptE, which are responsible for the final transport of the LPS across the membrane having most of the essential signature for being vaccine target. Both of these proteins are found highly conserved and possess shared surface epitopes among several species of Salmonella pathogens. This indicates that these two proteins could be the potential target for vaccine development, which could be effective for a broad range of Salmonella pathogens.

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Clinical challenges with hypervirulent Klebsiella pneumoniae (hvKP) in China

Journal of Translational Internal Medicine ◽

10.2478/jtim-2021-0004 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Yanzhu Chen ◽

Yi Chen

Keyword(s):

Antimicrobial Resistance ◽

Klebsiella Pneumoniae ◽

Published Data ◽

Clinical Microbiology Laboratory ◽

Consensus Definition ◽

Antibiotic Resistant ◽

Resistance Determinants ◽

The Past ◽

Resistant Strains ◽

Definition Of

AbstractHypervirulent Klebsiella pneumoniae (hvKp) is an evolving pathotype with higher virulence than classical K. pneumoniae (cKp) and is characterized by community-acquired, multiple sites of infections and young and healthy hosts. hvKP infections were primarily found in East Asia and have been increasingly reported worldwide over the past few decades. To better understand the clinical challenges faced by China with hvKP, this review will provide a summary and discussion focused on recognizing hvKP strains and prevalence of antibiotic-resistant hypervirulent strains in China and the mechanisms of acquiring antimicrobial resistance. Compared with cKP, hvKP is likely to cause serious disseminated infections, leading to a higher mortality. However, sensitive and specific clinical microbiology laboratory tests are still not available. Given the limited published data due to the clinical difficulty in differentiating hvKP from cKP, extrapolation of the previous data may not be applicable for the management of hvKP. A consensus definition of hvKP is needed. Furthermore, an increasing number of reports have described hvKp strains with antimicrobial resistance acquisition, increasing the challenges for management of hvKP. China, as an epidemic country, is also facing these challenges. Quite a number of studies from China have reported antibiotic-resistant hvKP strains, including extended-spectrum β-lactamase (ESBL), and carbapenem-, tigecycline-, and colistin-resistant strains. hvKP infections, especially those of antimicrobial-resistant strains, pose to be a great threat for public health in China. Therefore, an immediate response to recognize the hypervirulent strains and provide optimal treatments, especially those with resistance determinants, is an urgent priority for China.

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Integrating fish models in tuberculosis vaccine development

Disease Models & Mechanisms ◽

10.1242/dmm.045716 ◽

2020 ◽

Vol 13 (8) ◽

pp. dmm045716

Author(s):

Anni K. Saralahti ◽

Meri I. E. Uusi-Mäkelä ◽

Mirja T. Niskanen ◽

Mika Rämet

Keyword(s):

Immune Responses ◽

Vaccine Development ◽

Bacillus Calmette Guerin ◽

Antibiotic Resistant ◽

Vaccine Candidates ◽

Preclinical Evaluation ◽

Vaccination Strategies ◽

Resistant Strains ◽

New Vaccines

ABSTRACTTuberculosis is a chronic infection by Mycobacterium tuberculosis that results in over 1.5 million deaths worldwide each year. Currently, there is only one vaccine against tuberculosis, the Bacillus Calmette–Guérin (BCG) vaccine. Despite widespread vaccination programmes, over 10 million new M. tuberculosis infections are diagnosed yearly, with almost half a million cases caused by antibiotic-resistant strains. Novel vaccination strategies concentrate mainly on replacing BCG or boosting its efficacy and depend on animal models that accurately recapitulate the human disease. However, efforts to produce new vaccines against an M. tuberculosis infection have encountered several challenges, including the complexity of M. tuberculosis pathogenesis and limited knowledge of the protective immune responses. The preclinical evaluation of novel tuberculosis vaccine candidates is also hampered by the lack of an appropriate animal model that could accurately predict the protective effect of vaccines in humans. Here, we review the role of zebrafish (Danio rerio) and other fish models in the development of novel vaccines against tuberculosis and discuss how these models complement the more traditional mammalian models of tuberculosis.

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A history of the discovery of bacteriophages. Will the well - forgotten old become new?

Terapevt (General Physician) ◽

10.33920/med-12-2002-03 ◽

2020 ◽

pp. 21-26

Author(s):

E. Frolova

Keyword(s):

Antibacterial Agents ◽

Host Organism ◽

Pathogenic Microorganism ◽

Antibiotic Resistant ◽

Widespread Distribution ◽

Endocrine Diseases ◽

The Past ◽

History Of ◽

Resistant Strains

Staphylococcus is considered to be one of the most common pathogens that can lead to the development of numerous pathological processes, from pyoderma to peritonitis. Being a potentially pathogenic microorganism, it is able not to make itself noticed for years, peacefully coexisting with the host organism. But should one only go through a viral infection out of bed, suffer from stressful situations, or simply get overcooled, the potentially pathogenic microflora activates and manifests itself as a local or general infectious process. Activation of staphylococcal microflora is most often observed in sickly people with weakened immune systems, suffering from endocrine diseases, having long ellneses. Long-term and uncontrolled use of antibiotics with the formation of resistance to them is also of great importance. It is the widespread distribution of antibiotic-resistant strains of staphylococcus that makes doctors and scientists look for new forms of controling this and other microorganisms. Against this background, it’s time to recall the bacteriophages long forgotten in the era of the craze for antibiotics, especially given the fact that over the past thirty years not a single completely new group of antibacterial agents has been synthesized.

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Insights into the Bacterial Profiles and Resistome Structures Following the Severe 2018 Flood in Kerala, South India

Microorganisms ◽

10.3390/microorganisms7100474 ◽

2019 ◽

Vol 7 (10) ◽

pp. 474

Author(s):

Soumya Jaya Divakaran ◽

Jamiema Sara Philip ◽

Padma Chereddy ◽

Sai Ravi Chandra Nori ◽

Akshay Jaya Ganesh ◽

...

Keyword(s):

Pathogenic Bacteria ◽

Salmonella Typhi ◽

Multidrug Resistant ◽

Resistant Bacteria ◽

Southern State ◽

Antibiotic Resistant ◽

Shotgun Metagenomics ◽

Ecological Habitat ◽

Resistant Strains ◽

Extreme Flooding

Extreme flooding is one of the major risk factors for human health, and it can significantly influence the microbial communities and enhance the mobility of infectious disease agents within the affected areas. The flood crisis in 2018 was one of the severe natural calamities recorded in the southern state of India (Kerala) that significantly affected its economy and ecological habitat. We utilized a combination of shotgun metagenomics and bioinformatics approaches to understand the bacterial profile and the abundance of pathogenic and antibiotic-resistant bacteria in extremely flooded areas of Kuttanad, Kerala (4–10 feet below sea level). Here we report the bacterial profiles of flooded sites that are abundant with virulent and resistant bacteria. The flooded sites were heavily contaminated with faecal contamination indicators such as Escherichia coli and Enterococcus faecalis and multidrug-resistant strains of Pseudomonas aeruginosa, Salmonella typhi/typhimurium, Klebsiella pneumoniae, Vibrio cholerae. The resistome of the flooded sites contains 103 known resistant genes, of which 38% are plasmid-encoded, where most of them are known to be associated with pathogenic bacteria. Our results reveal an overall picture of the bacterial profile and resistome of sites following a devastating flood event, which might increase the levels of pathogens and its associated risks.

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Bacterial resistance to penicillins and cephalosporins

Proceedings of the Royal Society of London Series B Biological Sciences ◽

10.1098/rspb.1971.0105 ◽

1971 ◽

Vol 179 (1057) ◽

pp. 403-410 ◽

Cited By ~ 11

Keyword(s):

Bacterial Resistance ◽

Inhibitory Concentration ◽

The Body ◽

The Other ◽

Antibiotic Resistant ◽

The Past ◽

Thirtieth Anniversary ◽

The Subject ◽

Resistant Strains ◽

Points Of View

The subject of bacterial resistance to penicillins and cephalosporins could be discussed from a number of points of view and clearly it is not possible in the time available to review adequately every aspect. Some selection is necessary and bearing in mind that the Symposium commemorates the thirtieth anniversary of the introduction of penicillin into medicine it seemed to me that it would be appropriate to consider primarily the changes which have taken place over this period in the incidence of resistance and the knowledge which has been gained concerning the nature of resistance to this family of antibiotics. Before we look at what the changes in resistance have been, however, it may be useful to consider what one means by the word resistant, and in fact one uses the word in two rather different ways. Used in one sense the term applies to those species of bacteria which are characteristically insensitive to penicillin, for example one may say that Pseudomonas aeruginosa is resistant to benzylpenicillin, because this is a characteristic of the species. On the other hand, the term resistant is also applied to particular strains of species of bacteria which are typically penicillin sensitive, or at least were typically sensitive at the time penicillin was first introduced into medicine, for example penicillin-resistant strains of staphylococci and penicillinresistant gonococci. As a result of these two uses of the word resistant some anomalies appear to arise. For example, strains of Escherichia coli inhibited by ampicillin at a concentration of 2 μg/ml would certainly be considered sensitive, whereas strains of gonococci inhibited by one-tenth of this concentration would be regarded as resistant and this is because typical sensitive strains are inhibited by even lower levels. Again, strains of P s . aeruginosa requiring for inhibition a concentration of gentamicin of 10 μg/ml would be said to be resistant, but strains inhibited by carbenicillin at a level as high as 50 μg/ml are considered sensitive. Here the reason is toxicity: a level of 10 μg/ml of gentamicin could not safely be maintained in the body, whereas a level of 50 μg/ml carbenicillin can. Clearly there are two criteria for judging organisms to be resistant, one is that the concentration of drug required to inhibit growth is a level which cannot readily be achieved at the site of infection and the other is simply that the minimum inhibitory concentration is significantly higher than that of the majority of strains of that particular species. Resistance to penicillins and cephalosporins, as with other antibiotics, may arise in bacteria in one of two ways. Resistance may occur as a result of chromosomal mutation or it may arise as a result of the transfer of genetic information from a resistant bacterial cell to a sensitive cell and this transfer may take place by transformation or by conjugation or by the phage mediated process of transduction. Resistant strains, once they arise, may be at a selectional advantage when the drug is used and as a result they may become more prevalent. The frequency at which antibiotic resistant strains arise, and the rate at which they subsequently increase in numbers, varies greatly with different antibiotics and different pathogens and some of the changes in bacterial resistance to penicillins which have occurred over the past 30 years are shown in diagrammatic form in figure 1.

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Antibiotic treatment protocols revisited: The challenges of a conclusive assessment by mathematical modeling

10.1101/372938 ◽

2018 ◽

Cited By ~ 1

Author(s):

Hildegard Uecker ◽

Sebastian Bonhoeffer

Keyword(s):

Combination Therapy ◽

Bacterial Infections ◽

Treatment Protocols ◽

Antibiotic Resistant ◽

The Past ◽

Consistent Picture ◽

Hospital Stays ◽

Resistant Strains ◽

Prolonged Hospital ◽

Hospital Acquired

AbstractHospital-acquired bacterial infections lead to prolonged hospital stays and increased mortality. The problem is exacerbated by antibiotic resistant strains that delay or impede effective treatment. To ensure a successful therapy and to manage antibiotic resistance, treatment protocols that draw on several different antibiotics might be used. This includes the administration of drug cocktails to individual patients (“combination therapy”) but also the random assignment of drugs to different patients (“mixing”) and a regular switch in the default drug used in the hospital from drug A to drug B and back (“cycling”). For the past 20 years, mathematical models have been used to assess the prospects of antibiotic combination therapy, mixing, and cycling. But while tendencies in their ranking across studies have emerged, the picture remains surprisingly inconclusive and incomplete. In this article, we review existing modeling studies and demonstrate by means of examples how methodological factors complicate the emergence of a consistent picture. These factors include the choice of the criterion by which the effects of the protocols are compared, the model implementation, and its analysis. We thereafter discuss how progress can be made and suggest future modeling directions.

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Mechanisms involved in effects of antimicrobial peptides, bactenectins ChBac3.4, ChBac5, and mini-ChBac7.5Nb, on bacterial cells

Nauchno-prakticheskii zhurnal «Patogenez» ◽

10.25557/gm.2017.3.8496 ◽

2017 ◽

pp. 43-50

Author(s):

О.В. Шамова ◽

М.С. Жаркова ◽

П.М. Копейкин ◽

Д.С. Орлов ◽

Е.А. Корнева

Keyword(s):

Escherichia Coli ◽

Antimicrobial Activity ◽

Innate Immunity ◽

Infectious Diseases ◽

Metabolic Activity ◽

Capra Hircus ◽

Bacterial Cells ◽

Antibiotic Resistant ◽

Resistant Strains

Антимикробные пептиды (АМП) системы врожденного иммунитета - соединения, играющие важную роль в патогенезе инфекционных заболеваний, так как обладают свойством инактивировать широкий спектр патогенных бактерий, обеспечивая противомикробную защиту живых организмов. В настоящее время АМП рассматриваются как потенциальные соединения-корректоры инфекционной патологии, вызываемой антибиотикорезистентными бактериями (АБР). Цель данной работы состояла в изученим механизмов антибактериального действия трех пептидов, принадлежащих к семейству бактенецинов - ChBac3.4, ChBac5 и mini-ChBac7.5Nb. Эти химически синтезированные пептиды являются аналогами природных пролин-богатых АМП, обнаруженных в лейкоцитах домашней козы Capra hircus и проявляющих высокую антимикробную активность, в том числе и в отношении грамотрицательных АБР. Методы. Минимальные ингибирующие и минимальные бактерицидные концентрации пептидов (МИК и МБК) определяли методом серийных разведений в жидкой питательной среде с последующим высевом на плотную питательную среду. Эффекты пептидов на проницаемость цитоплазматической мембраны бактерий для хромогенного маркера исследовали с использованием генетически модифицированного штамма Escherichia coli ML35p. Действие бактенецинов на метаболическую активность бактерий изучали с применением маркера резазурина. Результаты. Показано, что все исследованные пептиды проявляют высокую антимикробную активность в отношении Escherichia coli ML35p и антибиотикоустойчивых штаммов Escherichia coli ESBL и Acinetobacter baumannii in vitro, но их действие на бактериальные клетки разное. Использован комплекс методик, позволяющих наблюдать в режиме реального времени динамику действия бактенецинов в различных концентрациях (включая их МИК и МБК) на барьерную функцию цитоплазматической мембраны и на интенсивность метаболизма бактериальных клеток, что дало возможность выявить различия в характере воздействия бактенецинов, отличающихся по структуре молекулы, на исследуемые микроорганизмы. Установлено, что действие каждого из трех исследованных бактенецинов в бактерицидных концентрациях отличается по эффективности нарушения целостности бактериальных мембран и в скорости подавления метаболизма клеток. Заключение. Полученная информация дополнит существующие фундаментальные представления о механизмах действия пролин-богатых пептидов врожденного иммунитета, а также послужит основой для биотехнологических исследований, направленных на разработку на базе этих соединений новых антибиотических препаратов для коррекции инфекционных заболеваний, вызываемых АБР и являющимися причинами тяжелых внутрибольничных инфекций. Antimicrobial peptides (AMPs) of the innate immunity are compounds that play an important role in pathogenesis of infectious diseases due to their ability to inactivate a broad array of pathogenic bacteria, thereby providing anti-microbial host defense. AMPs are currently considered promising compounds for treatment of infectious diseases caused by antibiotic-resistant bacteria. The aim of this study was to investigate molecular mechanisms of the antibacterial action of three peptides from the bactenecin family, ChBac3.4, ChBac5, and mini-ChBac7.5Nb. These chemically synthesized peptides are analogues of natural proline-rich AMPs previously discovered by the authors of the present study in leukocytes of the domestic goat, Capra hircus. These peptides exhibit a high antimicrobial activity, in particular, against antibiotic-resistant gram-negative bacteria. Methods. Minimum inhibitory and minimum bactericidal concentrations of the peptides (MIC and MBC) were determined using the broth microdilution assay followed by subculturing on agar plates. Effects of the AMPs on bacterial cytoplasmic membrane permeability for a chromogenic marker were explored using a genetically modified strain, Escherichia coli ML35p. The effect of bactenecins on bacterial metabolic activity was studied using a resazurin marker. Results. All the studied peptides showed a high in vitro antimicrobial activity against Escherichia coli ML35p and antibiotic-resistant strains, Escherichia coli ESBL and Acinetobacter baumannii, but differed in features of their action on bacterial cells. The used combination of techniques allowed the real-time monitoring of effects of bactenecin at different concentrations (including their MIC and MBC) on the cell membrane barrier function and metabolic activity of bacteria. The differences in effects of these three structurally different bactenecins on the studied microorganisms implied that these peptides at bactericidal concentrations differed in their capability for disintegrating bacterial cell membranes and rate of inhibiting bacterial metabolism. Conclusion. The obtained information will supplement the existing basic concepts on mechanisms involved in effects of proline-rich peptides of the innate immunity. This information will also stimulate biotechnological research aimed at development of new antibiotics for treatment of infectious diseases, such as severe in-hospital infections, caused by antibiotic-resistant strains.

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T-cell Epitope-based Vaccine Design for Nipah Virus by Reverse Vaccinology Approach

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207323666200427114343 ◽

2020 ◽

Vol 23 (8) ◽

pp. 788-796

Author(s):

Praveen K.P. Krishnamoorthy ◽

Sekar Subasree ◽

Udhayachandran Arthi ◽

Mohammad Mobashir ◽

Chirag Gowda ◽

...

Keyword(s):

T Cell ◽

Mhc Class Ii ◽

Vaccine Development ◽

Nipah Virus ◽

3D Structure ◽

Cell Epitope ◽

Class Ii ◽

Class I ◽

Reverse Vaccinology ◽

Stable Complex

Aim and Objective: Nipah virus (NiV) is a zoonotic virus of the paramyxovirus family that sporadically breaks out from livestock and spreads in humans through breathing resulting in an indication of encephalitis syndrome. In the current study, T cell epitopes with the NiV W protein antigens were predicted. Materials and Methods: Modelling of unavailable 3D structure of W protein followed by docking studies of respective Human MHC - class I and MHC - class II alleles predicted was carried out for the highest binding rates. In the computational analysis, epitopes were assessed for immunogenicity, conservation, and toxicity analysis. T – cell-based vaccine development against NiV was screened for eight epitopes of Indian - Asian origin. Results: Two epitopes, SPVIAEHYY and LVNDGLNII, have been screened and selected for further docking study based on toxicity and conservancy analyses. These epitopes showed a significant score of -1.19 kcal/mol and 0.15 kcal/mol with HLA- B*35:03 and HLA- DRB1 * 07:03, respectively by using allele - Class I and Class II from AutoDock. These two peptides predicted by the reverse vaccinology approach are likely to induce immune response mediated by T – cells. Conclusion: Simulation using GROMACS has revealed that LVNDGLNII epitope forms a more stable complex with HLA molecule and will be useful in developing the epitope-based Nipah virus vaccine.

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Screening of an FDA-Approved Library for Novel Drugs against Y. pestis

Antibiotics ◽

10.3390/antibiotics10010040 ◽

2021 ◽

Vol 10 (1) ◽

pp. 40

Author(s):

David Gur ◽

Theodor Chitlaru ◽

Emanuelle Mamroud ◽

Ayelet Zauberman

Keyword(s):

Drug Repurposing ◽

Mortality Rates ◽

Systematic Screening ◽

Antibiotic Resistant ◽

Gram Negative ◽

Therapy Initiation ◽

Novel Drugs ◽

Resistant Strains ◽

Approved Drugs ◽

Fda Approved Drugs

Yersinia pestis is a Gram-negative pathogen that causes plague, a devastating disease that kills millions worldwide. Although plague is efficiently treatable by recommended antibiotics, the time of antibiotic therapy initiation is critical, as high mortality rates have been observed if treatment is delayed for longer than 24 h after symptom onset. To overcome the emergence of antibiotic resistant strains, we attempted a systematic screening of Food and Drug Administration (FDA)-approved drugs to identify alternative compounds which may possess antibacterial activity against Y. pestis. Here, we describe a drug-repurposing approach, which led to the identification of two antibiotic-like activities of the anticancer drugs bleomycin sulfate and streptozocin that have the potential for designing novel antiplague therapy approaches. The inhibitory characteristics of these two drugs were further addressed as well as their efficiency in affecting the growth of Y. pestis strains resistant to doxycycline and ciprofloxacin, antibiotics recommended for plague treatment.

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