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.

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 In vivo activities of ceftriaxone and vancomycin against Borrelia spp. in the mouse brain and other sites.

1996 ◽  
Vol 40 (11) ◽  
pp. 2632-2636 ◽  
Author(s):  
R J Kazragis ◽  
L L Dever ◽  
J H Jorgensen ◽  
A G Barbour
Keyword(s):  
Body Weight ◽  
Lyme Disease ◽  
Positive Control ◽  
Negative Control ◽  
Scid Mice ◽  
Immunodeficient Mice ◽  
Infected Adult ◽  
The Brain

Borrelia burgdorferi, the agent of Lyme disease, and B. turicatae, a neurotropic agent of relapsing fever, are susceptible to vancomycin in vitro, with an MIC of 0.5 microgram/ml. To determine the activity of vancomycin in vivo, particularly in the brain, we infected adult immunocompetent BALB/c and immunodeficient CB-17 scid mice with B. burgdorferi or B. turicatae. The mice were then treated with vancomycin, ceftriaxone as a positive control, or normal saline as a negative control. The effectiveness of treatment was assessed by cultures of blood and brain and other tissues. Ceftriaxone at a dose of 25 mg/kg of body weight administered every 12 h for 7 to 10 days eliminated cultivable B. burgdorferi or B. turicatae from all BALB/c or scid mice in the study. Vancomycin at 30 mg/kg administered every 12 h was effective in eliminating infection from immunodeficient mice if treatment was started within 3 days of the onset of infection. If treatment with vancomycin was delayed for 7 days or more, vancomycin failed to eradicate infection with B. burgdorferi or B. turicatae from immunodeficient mice. The failure of vancomycin in eradicating established infections in immunodeficient mice was associated with the persistence of viable spirochetes in the brain during antibiotic treatment.

scholarly journals Synthesis and pharmacophore modeling of novel quinazolines bearing a biologically active sulfonamide moiety

2013 ◽  
Vol 63 (1) ◽  
pp. 1-18 ◽  
Author(s):  
Mostafa M. Ghorab ◽  
Zienab H. Ismail ◽  
Awwad A. Radwan ◽  
Mohamad Abdalla
Keyword(s):  
Aromatic Aldehydes ◽  
Antimicrobial Activities ◽  
Pharmacophore Modeling ◽  
Positive Control ◽  
Biologically Active ◽  
Significant Activity ◽  
Sulfa Drugs ◽  
Amino Derivatives ◽  
Work Interaction

In the present work, interaction of the strategic starting material, methyl 2-isothiocyanatobenzoate (1), with sulfa drugs resulted in the formation of methyl 2-[3-(4-(N-substituted sulfamoyl)phenyl)thioureido] benzoates 2-5, which upon reaction with hydrazine hydrate afforded N-amino derivatives 6-9. Triazoloquinazoline derivatives 10-18 were obtained via reaction of compounds 6-8 with aromatic aldehydes. Also, the reaction of compound 8 with formic acid gave the corresponding triazoloquinazoline derivative 19. Triazinoquinazoline derivatives 22, 23 were obtained via reaction of N-amino derivatives 6 or 8 with ethyl chloroacetate. Interaction of 6 with diethyloxalate yielded triazoloquinazoline 26. The synthesized compounds were screened for their in vitro antimicrobial activities and some of them exhibited promising antibacterial activity compared to ampicillin as positive control. Compounds that revealed significant activity are able to satisfy effectively the proposed pharmacophore geometry.

scholarly journals Activity of Sulfa Drugs and Their Combinations against Stationary Phase B. burgdorferi In Vitro

Antibiotics ◽  
2017 ◽  
Vol 6 (1) ◽  
pp. 10 ◽  
Author(s):  
Jie Feng ◽  
Shuo Zhang ◽  
Wanliang Shi ◽  
Ying Zhang
Keyword(s):  
Stationary Phase ◽  
Sulfa Drugs

scholarly journals Bactericidal action of ofloxacin, sulbactam-ampicillin, rifampin, and isoniazid on logarithmic- and stationary-phase cultures of Mycobacterium tuberculosis.

1996 ◽  
Vol 40 (10) ◽  
pp. 2296-2299 ◽  
Author(s):  
D Herbert ◽  
C N Paramasivan ◽  
P Venkatesan ◽  
G Kubendiran ◽  
R Prabhakar ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Stationary Phase ◽  
Bactericidal Activity ◽  
Exponential Phase ◽  
Drug Combinations ◽  
Bactericidal Action ◽  
Level Of Activity ◽  
Susceptible Isolate ◽  
Emergence Of Resistance

The bactericidal actions of ofloxacin and sulbactam-ampicillin, alone and in combination with rifampin and isoniazid, on exponential-phase and stationary-phase cultures of a drug-susceptible isolate of Mycobacterium tuberculosis were studied in vitro. In exponential-phase cultures, all drugs were bactericidal, with the higher concentrations of ofloxacin (5 micrograms/ml) and sulbactam-ampicillin (15 micrograms of ampicillin per ml) being as bactericidal as 1 microgram of isoniazid per ml or 1 microgram of rifampin per ml. In two-drug combinations, both drugs increased the levels of activity of isoniazid and rifampin and were almost as bactericidal as isoniazid-rifampin; they also appeared to increase the level of activity of isoniazid-rifampin in three-drug combinations. In contrast, ofloxacin and sulbactam-ampicillin had little bactericidal activity against stationary-phase cultures and were less active than isoniazid or rifampin alone. Furthermore, in two-drug or three-drug combinations, they did not increase the level of activity of isoniazid, rifampin, or isoniazid-rifampin. These findings suggest that ofloxacin and sulbactam-ampicillin are likely to be most useful in the early stages of treatment and in preventing the emergence of resistance to other drugs but are unlikely to be effective as sterilizing drugs helping to kill persisting lesional bacilli.

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 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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