scholarly journals Evaluation of Disulfiram Drug Combinations and Identification of Other More Effective Combinations against Stationary Phase Borrelia burgdorferi

Antibiotics ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 542 ◽  
Author(s):  
Hector Alvarez-Manzo ◽  
Yumin Zhang ◽  
Wanliang Shi ◽  
Ying Zhang
Keyword(s):  
Lyme Disease ◽  
Borrelia Burgdorferi ◽  
Stationary Phase ◽  
Drug Exposure ◽  
Drug Combinations ◽  
Persistent Symptoms ◽  
Exposure Experiment ◽  
Vector Borne ◽  
Treatment Alternatives ◽  
Possible Cause

Lyme disease, caused by Borrelia burgdorferi, is the most common vector-borne disease in USA, and 10–20% of patients will develop persistent symptoms despite treatment (“post-treatment Lyme disease syndrome”). B. burgdorferi persisters, which are not killed by the current antibiotics for Lyme disease, are considered one possible cause. Disulfiram has shown to be active against B. burgdorferi, but its activity against persistent forms is not well characterized. We assessed disulfiram as single drug and in combinations against stationary-phase B. burgdorferi culture enriched with persisters. Disulfiram was not very effective in the drug exposure experiment (survival rate (SR) 46.3%) or in combinations. Clarithromycin (SR 41.1%) and nitroxoline (SR 37.5%) were equally effective when compared to the current Lyme antibiotic cefuroxime (SR 36.8%) and more active than disulfiram. Cefuroxime + clarithromycin (SR 25.9%) and cefuroxime + nitroxoline (SR 27.5%) were significantly more active than cefuroxime + disulfiram (SR 41.7%). When replacing disulfiram with clarithromycin or nitroxoline in three-drug combinations, bacterial viability decreased significantly and subculture studies showed that combinations with these two drugs (cefuroxime + clarithromycin/nitroxoline + furazolidone/nitazoxanide) inhibited the regrowth, while disulfiram combinations did not (cefuroxime + disulfiram + furazolidone/nitazoxanide). Thus, clarithromycin and nitroxoline should be further assessed to determine their role as potential treatment alternatives in the future.

scholarly journals Nitroxoline as a promising alternative drug for the treatment of Lyme disease based on an in-vitro study

2021 ◽  
Author(s):  
Hector S. Alvarez-Manzo ◽  
Yumin Zhang ◽  
Wanliang Shi ◽  
Ying Zhang
Keyword(s):  
Lyme Disease ◽  
Stationary Phase ◽  
Drug Exposure ◽  
Drug Combinations ◽  
Stationary Phase Culture ◽  
Promising Alternative ◽  
Alternative Drug ◽  
Tract Infections

AbstractLyme disease (LD) is the most common vector-borne disease in USA and Europe and is caused by Borrelia burgdorferi. Despite proper treatment, approximately one fifth of patients will develop post-treatment LD syndrome (PTLDS), a condition which is poorly understood. One of the possible causes is thought to be due to persister forms of B. burgdorferi that are not effectively killed by the current Lyme antibiotics. In this study, we evaluated nitroxoline, an antibiotic used to treat urinary tract infections, for its activity against a stationary-phase culture enriched with persister forms of B. burgdorferi. Nitroxoline was found to be equivalent in activity against B. burgdorferi to cefuroxime (standard Lyme antibiotic) in different experiments. Moreover, we found that the three-drug combination cefuroxime + nitroxoline + clarithromycin eradicated 98.3% of stationary phase bacteria in the drug-exposure experiment and prevented the regrowth in the subculture study after drug exposure, as well as two-drug combinations cefuroxime + nitroxoline and clarithromycin + nitroxoline. These drug combinations should be further evaluated in a LD mouse model to assess if eradication of persister forms of B. burgdorferi in-vivo is possible and if so, whether nitroxoline could be repurposed as an alternative drug for the treatment of LD.

scholarly journals Activity of Sulfa Drugs and Their Combinations against Stationary PhaseB. burgdorferiin vitro

2017 ◽  
Author(s):  
Jie Feng ◽  
Shuo Zhang ◽  
Wanliang Shi ◽  
Ying Zhang
Keyword(s):  
Lyme Disease ◽  
Stationary Phase ◽  
Relative Activity ◽  
Positive Control ◽  
Drug Combinations ◽  
Sulfa Drugs ◽  
Sulfa Drug ◽  
The Us ◽  
Vector Borne

AbstractLyme disease is a most common vector borne disease in the US. Although the majority of Lyme patients can be cured with the standard 2-4 week antibiotic treatment, at least 10-20% of patients continue to suffer from prolonged post-treatment Lyme disease syndrome (PTLDS). While the cause for this is unclear, one possibility is that persisting organisms are not killed by current Lyme antibiotics. In our previous studies, we screened an FDA drug library and an NCI compound library onB. burgdorferiand found some drug hits including sulfa drugs as having good activity againstB. burgdorferistationary phase cells. In this study, we evaluated the relative activity of three commonly used sulfa drugs sulfamethoxazole (Smx), dapsone (Dps), sulfachlorpyridazine (Scp), and also trimethoprim (Tmp), and assessed their combinations with the commonly prescribed Lyme antibiotics for activities againstB. burgdorferistationary phase cells. Using the same molarity concentration, dapsone, sulfachlorpyridazine and trimethoprim showed very similar activity against stationary phaseB. burgdorferienriched in persisters, however, sulfamethoxazole was the least active drug among the three sulfa drugs tested. Interestingly, contrary to other bacterial systems, Tmp did not show synergy in drug combinations with the three sulfa drugs at their clinically relevant serum concentrations againstB. burgdorferi. We found that sulfa drugs combined with other antibiotics were more active than their respective single drugs and that four-drug combinations were more active than three-drug combinations. Four drug combinations dapsone+minocycline+cefuroxime+azithromycin and dapsone+minocycline+cefuroxime+rifampin showed best activity against stationary phaseB. burgdorferiin these sulfa drug combinations. However, these 4-sulfa drug containing combinations still had considerably less activity againstB. burgdorferistationary phase cells than the daptomycin+cefuroxime+doxycycline used as a positive control which completely eradicatedB. burgdorferistationary phase cells. Future studies are needed to evaluate and optimize the sulfa drug combinationsin vitroand also in animal models.

Do birds affect Lyme disease risk? Range expansion of the vector‐borne pathogen Borrelia burgdorferi

2009 ◽  
Vol 9 (2) ◽  
pp. 103-110 ◽  
Author(s):  
R Jory Brinkerhoff ◽  
Corrine M Folsom-O'Keefe ◽  
Kimberly Tsao ◽  
Maria A Diuk-Wasser
Keyword(s):  
Lyme Disease ◽  
Borrelia Burgdorferi ◽  
Range Expansion ◽  
Disease Risk ◽  
Vector Borne ◽  
Lyme Disease Risk

scholarly journals Recent Progress in Lyme Disease and Remaining Challenges

2021 ◽  
Vol 8 ◽  
Author(s):  
Jason R. Bobe ◽  
Brandon L. Jutras ◽  
Elizabeth J. Horn ◽  
Monica E. Embers ◽  
Allison Bailey ◽  
...  
Keyword(s):  
United States ◽  
Lyme Disease ◽  
Molecular Mechanisms ◽  
The United States ◽  
Persistent Symptoms ◽  
Number Of Patients ◽  
Vector Borne ◽  
The Many ◽  
Long Term Impact ◽  
Patients Experience

Lyme disease (also known as Lyme borreliosis) is the most common vector-borne disease in the United States with an estimated 476,000 cases per year. While historically, the long-term impact of Lyme disease on patients has been controversial, mounting evidence supports the idea that a substantial number of patients experience persistent symptoms following treatment. The research community has largely lacked the necessary funding to properly advance the scientific and clinical understanding of the disease, or to develop and evaluate innovative approaches for prevention, diagnosis, and treatment. Given the many outstanding questions raised into the diagnosis, clinical presentation and treatment of Lyme disease, and the underlying molecular mechanisms that trigger persistent disease, there is an urgent need for more support. This review article summarizes progress over the past 5 years in our understanding of Lyme and tick-borne diseases in the United States and highlights remaining challenges.

scholarly journals Association between Sudden Sensorineural Hearing Loss and Lyme Disease

2021 ◽  
Vol 10 (5) ◽  
pp. 1130
Author(s):  
Klaudia Sowula ◽  
Joanna Szaleniec ◽  
Kamila Stolcman ◽  
Piotr Ceranowicz ◽  
Sebastian Kocoń ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Lyme Disease ◽  
Borrelia Burgdorferi ◽  
Sensorineural Hearing Loss ◽  
Sudden Sensorineural Hearing Loss ◽  
Sensorineural Hearing ◽  
Borrelia Burgdorferi Sensu Lato ◽  
Complete Regression ◽  
Serological Tests ◽  
Possible Cause

Objectives: Sudden sensorineural hearing loss (SSNHL) is defined as sensorineural hearing loss of 30 dB or more over at least three adjacent audiometric frequencies occurring within a 72-h period of time. One of the causes of SSNHL could be the progressive inflammatory state caused by an infection. The aim of this study was to assess the prevalence of SSNHL caused by various factors, most importantly those potentially related to Lyme disease. Material and Methods: The study includes a group of 86 patients between the ages of 20 and 70 who were hospitalized due to SSNHL between 2017 and 2018. All of these patients underwent a detailed medical interview and an otolaryngological examination, including audiological and diagnostic tests. Additionally, ELISA and Western blot tests were performed to confirm the diagnosis of Lyme disease. Results: In this group of 86 patients, nine patients presented with positive antibodies toward Borrelia burgdorferi sensu lato. This group was treated with antibiotics and experienced partial or complete regression of their deafness. This may suggest a relationship between SSNHL and Lyme disease. Conclusion: Infections caused by Borrelia burgdorferi may contribute to the development of inflammatory and angiopathic lesions, which are a possible cause of SSNHL. The longer the duration of the infection, the greater the likelihood of permanent and irreversible changes in the vessels of the cochlea or auditory nerve. Therefore, serological tests for Borrelia burgdorferi should be performed during the diagnosis of SSNHL as a possible cause of this illness.

scholarly journals Proteomic Analyses of Morphological Variants ofBorrelia burgdorferiShed New Light on Persistence Mechanisms: Implications for Pathogenesis, Diagnosis and Treatment

2018 ◽  
Author(s):  
Jie Feng ◽  
Ying Zhang
Keyword(s):  
Lyme Disease ◽  
Stationary Phase ◽  
Cell Envelope ◽  
The United States ◽  
Planktonic Form ◽  
Vector Borne ◽  
Morphological Variants ◽  
Mechanisms Of Persistence ◽  
Related Proteins ◽  
Shed Light

AbstractBorrelia burgdorfericauses Lyme disease, which is the most common vector borne disease in the United States and Europe. Although 2-4 week antibiotic treatment for Lyme disease is effective in the majority of cases, about 10–20% patients suffer from prolonged post-treatment Lyme disease syndrome (PTLDS). While the mechanisms of PTLDS are unclear, persisting organisms not killed by current Lyme antibiotics has been suggested as a possible explanation.B. burgdorferican spontaneously develop different morphological variant forms under stress or in stationary phase with increased persistence to antibiotics. To shed light on the possible mechanisms by which these variant forms develop persistence, here, we isolated threeB. burgdorferiforms, log phase spirochetal form, stationary phase planktonic form, and stationary phase aggregated biofilm-like microcolony form. We showed that the two separated stationary phase forms especially microcolony form have more persistence to antibiotics than the log phase spirochetal form. Then, we performed mass spectrometry (MS/MS) analysis to determine the proteomic profiles of the three different forms to reveal the mechanisms of persistence inB. burgdorferi. We identified 1023 proteins in the threeB. burgdorferiforms, with 642 proteins (63%) differentially expressed. Compared with the log phase spirochetal form ofB. burgdorferi, a total of 143 proteins were upregulated in both stationary phase planktonic form and microcolony form. Among these common upregulated proteins, 90 proteins had predicted functions and were mapped to different pathways involved in infection and virulence, DNA repair, heat shock, transport, sporulation, cell envelope and metabolism, many of which are consistent with persister mechanisms in other bacteria. A particularly interesting observation is that infection and virulence related proteins are highly up-regulated in stationary phase planktonic form and microcolony form compared with log phase spirochetal form. These findings shed new light on the mechanisms ofB. burgdorferipersistence and offer novel targets for developing more effective diagnostics, vaccines and treatments.

scholarly journals Extraction and Fractionation of Bioactives from Dipsacus fullonum L. Leaves and Evaluation of Their Anti-Borrelia Activity

2022 ◽  
Vol 15 (1) ◽  
pp. 87
Author(s):  
Piret Saar-Reismaa ◽  
Olga Bragina ◽  
Maria Kuhtinskaja ◽  
Indrek Reile ◽  
Pille-Riin Laanet ◽  
...  
Keyword(s):  
Lyme Disease ◽  
Borrelia Burgdorferi ◽  
Stationary Phase ◽  
High Activity ◽  
Iridoid Glycoside ◽  
Bacterial Disease ◽  
3T3 Cells ◽  
Murine Fibroblast ◽  
Nih 3T3

Lyme disease (LD) is a tick-borne bacterial disease that is caused by Borrelia burgdorferi. Although acute LD is treated with antibiotics, it can develop into relapsing chronic form caused by latent forms of B. burgdorferi. This leads to the search for phytochemicals against resistant LD. Therefore, this study aimed to evaluate the activity of Dipsacus fullonum L. leaves extract (DE) and its fractions against stationary phase B. burgdorferi in vitro. DE showed high activity against stationary phase B. burgdorferi (residual viability 19.8 ± 4.7%); however, it exhibited a noticeable cytotoxicity on NIH cells (viability 20.2 ± 5.2%). The iridoid-glycoside fraction showed a remarkable anti-Borrelia effect and reduced cytotoxicity. The iridoid-glycoside fraction was, therefore, further purified and showed to contain two main bioactives—sylvestrosides III and IV, that showed a considerable anti-Borrelia activity being the least toxic to murine fibroblast NIH/3T3 cells. Moreover, the concentration of sylvestrosides was about 15% of DE, endorsing the feasibility of purification of the compounds from D. fullonum L. leaves.

scholarly journals Anti-Borrelia burgdorferi Antibody Profile in Post-Lyme Disease Syndrome

2011 ◽  
Vol 18 (5) ◽  
pp. 767-771 ◽  
Author(s):  
Abhishek Chandra ◽  
Gary P. Wormser ◽  
Adriana R. Marques ◽  
Norman Latov ◽  
Armin Alaedini
Keyword(s):  
Lyme Disease ◽  
Borrelia Burgdorferi ◽  
Content Type ◽  
Healthy Group ◽  
Persistent Symptoms ◽  
History Of ◽  
Serologic Evidence ◽  
Antecedent Infection ◽  
Antibody Profile ◽  
Or History

ABSTRACTPatients with post-Lyme disease syndrome (PLDS) report persistent symptoms of pain, fatigue, and/or concentration and memory disturbances despite antibiotic treatment for Lyme borreliosis. The etiopathogenesis of these symptoms remains unknown and no effective therapies have been identified. We sought to examine the antiborrelia antibody profile in affected patients with the aim of finding clues to the mechanism of the syndrome and its relationship to the original spirochetal infection. Serum specimens from 54 borrelia-seropositive PLDS patients were examined for antibodies toBorrelia burgdorferiproteins p18, p25, p28, p30, p31, p34, p39, p41, p45, p58, p66, p93, and VlsE by automated immunoblotting and software-assisted band analysis. The presence of serum antibodies to the 31-kDa band was further investigated by examination of reactivity against purified recombinant OspA protein. Control specimens included sera from 14 borrelia-seropositive individuals with a history of early localized or disseminated Lyme disease who were symptom free (post-Lyme healthy group), as well as 20 healthy individuals without serologic evidence or history of Lyme disease. In comparison to the post-Lyme healthy group, higher frequencies of antibodies to p28 (P< 0.05), p30 (P< 0.05), p31 (P< 0.0001), and p34 (P< 0.05) proteins were found in the PLDS group. Assessment of antibody reactivity to recombinant OspA confirmed the presence of elevated levels in PLDS patients (P< 0.005). The described antiborrelia antibody profile in PLDS offers clues about the course of the antecedent infection in affected patients, which may be useful for understanding the pathogenic mechanism of the disease.

scholarly journals Vaccination against Lyme disease caused by diverse Borrelia burgdorferi.

1995 ◽  
Vol 181 (1) ◽  
pp. 215-221 ◽  
Author(s):  
E Fikrig ◽  
S R Telford ◽  
R Wallich ◽  
M Chen ◽  
Y Lobet ◽  
...  
Keyword(s):  
Lyme Disease ◽  
Borrelia Burgdorferi ◽  
Classification Systems ◽  
Surface Proteins ◽  
Borrelia Burgdorferi Sensu Lato ◽  
Natural Mode ◽  
Naturally Occurring ◽  
Vector Borne

Diversity and mutations in the genes for outer surface proteins (Osps) A and B of Borrelia burgdorferi sensu lato (B. burgdorferi), the spirochetal agent of Lyme disease, suggests that a monovalent OspA or OspB vaccine may not provide protection against antigenically variable naturally occurring B. burgdorferi. We now show that OspA or OspB immunizations protect mice from tick-borne infection with heterogeneous B. burgdorferi from different geographic regions. This result is in distinct contrast to in vitro killing analyses and in vivo protection studies using syringe injections of B. burgdorferi as the challenge inoculum. Evaluations of vaccine efficacy against Lyme disease and other vector-borne infections should use the natural mode of transmission and not be predicated on classification systems or assays that do not rely upon the vector to transmit infection.

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