Postexposure Administration of a Yersinia pestis Live Vaccine for Potentiation of Second-Line Antibiotic Treatment Against Pneumonic Plague

2019 ◽  
Vol 220 (7) ◽  
pp. 1147-1151 ◽  
Author(s):  
Ayelet Zauberman ◽  
David Gur ◽  
Yinon Levy ◽  
Moshe Aftalion ◽  
Yaron Vagima ◽  
...  
Keyword(s):  
Yersinia Pestis ◽  
Antibiotic Treatment ◽  
Second Line ◽  
Proof Of Concept ◽  
Antibiotic Resistant ◽  
Pneumonic Plague ◽  
Iron Sequestration ◽  
Resistant Strains ◽  
Respiratory Challenge ◽  
Temporary Inhibition

Abstract Pneumonic plague, caused by Yersinia pestis, is a rapidly progressing contagious disease. In the plague mouse model, a single immunization with the EV76 live attenuated Y. pestis strain rapidly induced the expression of hemopexin and haptoglobin in the lung and serum, both of which are important in iron sequestration. Immunization against a concomitant lethal Y. pestis respiratory challenge was correlated with temporary inhibition of disease progression. Combining EV76-immunization and second-line antibiotic treatment, which are individually insufficient, led to a synergistic protective effect that represents a proof of concept for efficient combinational therapy in cases of infection with antibiotic-resistant strains.

scholarly journals Antibiotic resistant staphylococci acquired during the first year of life

1978 ◽  
Vol 81 (1) ◽  
pp. 125-130 ◽  
Author(s):  
M. L. Burr ◽  
C. H. L. Howells ◽  
P. W. J. Rees
Keyword(s):  
Staphylococcus Aureus ◽  
Antibiotic Treatment ◽  
First Year ◽  
Antibiotic Resistant ◽  
South Wales ◽  
Maternity Hospitals ◽  
Nasal Swabs ◽  
Resistant Strains ◽  
Discharge From Hospital ◽  
First Year Of Life

SUMMARYNasal swabs were taken from 492 babies born consecutively to residents of two South Wales towns soon after their discharge from maternity hospitals. Staphylococcus aureus was isolated from 352 babies (72%) and in 79 (22%) of these it was resistant to at least one antibiotic. By the time these babies were a year old the prevalence of both sensitive and resistant strains had fallen, so that only 12% still carried nasal staphylococci, but 64% of these organisms were then resistant to penicillin. Administration of penicillin to the baby seemed to be a more important factor in selecting resistant organisms than other antibiotics given to the baby, any antibiotic treatment to other members of the household, or discharge from hospital.

scholarly journals Yersinia pestis CO92ΔyopH Is a Potent Live, Attenuated Plague Vaccine

2007 ◽  
Vol 14 (9) ◽  
pp. 1235-1238 ◽  
Author(s):  
Sarah S. Bubeck ◽  
Peter H. Dube
Keyword(s):  
Yersinia Pestis ◽  
Live Attenuated Vaccine ◽  
Pneumonic Plague ◽  
Degree Of Protection ◽  
Attenuated Vaccine ◽  
Respiratory Challenge ◽  
High Degree ◽  
Plague Vaccine

ABSTRACT An in-frame deletion of the yopH gene in Yersinia pestis CO92 attenuates virulence in both bubonic and pneumonic plague models. When it is used as a live, attenuated vaccine, CO92ΔyopH provides a high degree of protection from parental and respiratory challenge with Y. pestis CO92.

scholarly journals New Insights into Autoinducer-2 Signaling as a Virulence Regulator in a Mouse Model of Pneumonic Plague

mSphere ◽  
2016 ◽  
Vol 1 (6) ◽  
Author(s):  
Eric C. Fitts ◽  
Jourdan A. Andersson ◽  
Michelle L. Kirtley ◽  
Jian Sha ◽  
Tatiana E. Erova ◽  
...  
Keyword(s):  
Mouse Model ◽  
Yersinia Pestis ◽  
Bacterial Virulence ◽  
Resistant Bacteria ◽  
Antibiotic Resistant Bacteria ◽  
Global Crisis ◽  
Antibiotic Resistant ◽  
Pneumonic Plague ◽  
Content Type ◽  
Autoinducer 2

ABSTRACT Yersinia pestis is the bacterial agent that causes the highly fatal disease plague. The organism represents a significant concern because of its potential use as a bioterror agent, beyond the several thousand naturally occurring human infection cases occurring globally each year. While there has been development of effective antibiotics, the narrow therapeutic window and challenges posed by the existence of antibiotic-resistant strains represent serious concerns. We sought to identify novel virulence factors that could potentially be incorporated into an attenuated vaccine platform or be targeted by novel therapeutics. We show here that a highly conserved quorum-sensing system, autoinducer-2, significantly affected the virulence of Y. pestis in a mouse model of pneumonic plague. We also identified steps in autoinducer-2 signaling which had confounded previous studies and demonstrated the potential for intervention in the virulence mechanism(s) of autoinducer-2. Our findings may have an impact on bacterial pathogenesis research in many other organisms and could result in identifying potential broad-spectrum therapeutic targets to combat antibiotic-resistant bacteria, which represent a global crisis of the 21st century. The Enterobacteriaceae family members, including the infamous Yersinia pestis, the causative agent of plague, have a highly conserved interbacterial signaling system that is mediated by the autoinducer-2 (AI-2) quorum-sensing molecule. The AI-2 system is implicated in regulating various bacterial virulence genes in diverse environmental niches. Deletion of the gene encoding the synthetic enzyme for the AI-2 substrate, luxS, leads to either no significant change or, paradoxically, an increase in in vivo bacterial virulence. We showed that deletion of the rbsA and lsrA genes, components of ABC transport systems that interact with AI-2, synergistically disrupted AI-2 signaling patterns and resulted in a more-than-50-fold decrease in Y. pestis strain CO92 virulence in a stringent pneumonic plague mouse model. Deletion of luxS or lsrK (encoding AI-2 kinase) from the ΔrbsA ΔlsrA background strain or complementation of the ΔrbsA ΔlsrA mutant with the corresponding gene(s) reverted the virulence phenotype to that of the wild-type Y. pestis CO92. Furthermore, the administration of synthetic AI-2 in mice infected with the ΔrbsA ΔlsrA ΔluxS mutant strain attenuated this triple mutant to a virulence phenotype similar to that of the ΔrbsA ΔlsrA strain in a pneumonic plague model. Conversely, the administration of AI-2 to mice infected with the ΔrbsA ΔlsrA ΔluxS ΔlsrK mutant did not rescue animals from lethality, indicating the importance of the AI-2–LsrK axis in regulating bacterial virulence. By performing high-throughput RNA sequencing, the potential role of some AI-2-signaling-regulated genes that modulated bacterial virulence was determined. We anticipate that the characterization of AI-2 signaling in Y. pestis will lead to reexamination of AI-2 systems in other pathogens and that AI-2 signaling may represent a broad-spectrum therapeutic target to combat antibiotic-resistant bacteria, which represent a global crisis of the 21st century. IMPORTANCE Yersinia pestis is the bacterial agent that causes the highly fatal disease plague. The organism represents a significant concern because of its potential use as a bioterror agent, beyond the several thousand naturally occurring human infection cases occurring globally each year. While there has been development of effective antibiotics, the narrow therapeutic window and challenges posed by the existence of antibiotic-resistant strains represent serious concerns. We sought to identify novel virulence factors that could potentially be incorporated into an attenuated vaccine platform or be targeted by novel therapeutics. We show here that a highly conserved quorum-sensing system, autoinducer-2, significantly affected the virulence of Y. pestis in a mouse model of pneumonic plague. We also identified steps in autoinducer-2 signaling which had confounded previous studies and demonstrated the potential for intervention in the virulence mechanism(s) of autoinducer-2. Our findings may have an impact on bacterial pathogenesis research in many other organisms and could result in identifying potential broad-spectrum therapeutic targets to combat antibiotic-resistant bacteria, which represent a global crisis of the 21st century.

scholarly journals The ABC Transporter Protein OppA Provides Protection against Experimental Yersinia pestis Infection

2006 ◽  
Vol 74 (6) ◽  
pp. 3687-3691 ◽  
Author(s):  
Mikio Tanabe ◽  
Helen S. Atkins ◽  
David N. Harland ◽  
Stephen J. Elvin ◽  
Anthony J. Stagg ◽  
...  
Keyword(s):  
Yersinia Pestis ◽  
Western Blotting ◽  
Abc Transporter ◽  
Immunoglobulin G ◽  
Antibiotic Resistant ◽  
Transporter Proteins ◽  
Time To Death ◽  
Transporter Protein ◽  
Resistant Strains ◽  
Bioterrorism Agent

ABSTRACT The identification of Yersinia pestis as a potential bioterrorism agent and the emergence of antibiotic-resistant strains have highlighted the need for improved vaccines and treatments for plague. The aim of this study was to evaluate the potential for ATP-binding cassette (ABC) transporter proteins to be exploited as novel vaccines against plague. Western blotting of ABC transporter proteins using sera from rabbits immunized with killed whole Y. pestis cells or human convalescent-phase sera identified four immunologically reactive proteins: OppA, PstS, YrbD, and PiuA. Mice immunized with these proteins developed antibody to the immunogen. When the immunized mice were challenged with Y. pestis, the OppA-immunized mice showed an increased time to death compared to other groups, and protection appeared to correlate with the level of immunoglobulin G antibody to OppA.

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

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.

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

Antibiotics ◽  
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.

scholarly journals Vaccination with Outer Membrane Complexes Elicits Rapid Protective Immunity to Multidrug-ResistantAcinetobacter baumannii

2010 ◽  
Vol 79 (1) ◽  
pp. 518-526 ◽  
Author(s):  
Michael J. McConnell ◽  
Juan Domínguez-Herrera ◽  
Younes Smani ◽  
Rafael López-Rojas ◽  
Fernando Docobo-Pérez ◽  
...  
Keyword(s):  
Outer Membrane ◽  
Protective Immunity ◽  
Cellular Responses ◽  
Antibiotic Resistant ◽  
Membrane Complex ◽  
Sepsis Model ◽  
Cytokine Levels ◽  
Prophylactic Vaccination ◽  
Resistant Strains ◽  
Established Infection

ABSTRACTAcinetobacter baumanniicauses pneumonias, bacteremias, and skin and soft tissue infections, primarily in the hospitalized setting. The incidence of infections caused byA. baumanniihas increased dramatically over the last 30 years, while at the same time the treatment of these infections has been complicated by the emergence of antibiotic-resistant strains. Despite these trends, no vaccines or antibody-based therapies have been developed for the prevention ofA. baumanniiinfection. In this study, an outer membrane complex vaccine consisting of multiple surface antigens from the bacterial membrane ofA. baumanniiwas developed and tested in a murine sepsis model. Immunization elicited humoral and cellular responses that were able to reduce postinfection bacterial loads, reduce postinfection proinflammatory cytokine levels in serum, and protect mice from infection with human clinical isolates ofA. baumannii. A single administration of the vaccine was able to elicit protective immunity in as few as 6 days postimmunization. In addition, vaccine antiserum was used successfully to therapeutically rescue naïve mice with established infection. These results indicate that prophylactic vaccination and antibody-based therapies based on an outer membrane complex vaccine may be viable approaches to preventing the morbidity and mortality caused by this pathogen.

scholarly journals Evidence of Another Anthropic Impact on Iguana delicatissima from the Lesser Antilles: The Presence of Antibiotic Resistant Enterobacteria

Antibiotics ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 885
Author(s):  
Gustavo Di Lallo ◽  
Marco Maria D’Andrea ◽  
Samanta Sennati ◽  
Maria Cristina Thaller ◽  
Luciana Migliore ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Animal Species ◽  
Susceptibility Testing ◽  
Acquired Resistance ◽  
Climatic Conditions ◽  
Antibiotic Resistant ◽  
Associated Bacteria ◽  
Improper Use ◽  
Resistant Strains ◽  
Drug Resistant Strains

The improper use of antibiotics by humans may promote the dissemination of resistance in wildlife. The persistence and spread of acquired antibiotic resistance and human-associated bacteria in the environment, while representing a threat to wildlife, can also be exploited as a tool to monitor the extent of human impact, particularly on endangered animal species. Hence, we investigated both the associated enterobacterial species and the presence of acquired resistance traits in the cloacal microbiota of the critically endangered lesser Antillean iguana (Iguana delicatissima), by comparing two separate populations living in similar climatic conditions but exposed to different anthropic pressures. A combination of techniques, including direct plating, DNA sequencing and antimicrobial susceptibility testing allowed us to characterize the dominant enterobacterial populations, the antibiotic resistant strains and their profiles. A higher frequency of Escherichia coli was found in the samples from the more anthropized site, where multi-drug resistant strains were also isolated. These results confirm how human-associated bacteria as well as their antibiotic-resistance determinants may be transferred to wildlife, which, in turn, may act as a reservoir of antibiotic resistance.

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