Identification of new drug candidates against Borrelia burgdorferi using high-throughput screening

Pothineni, Venkata Raveendra; Wagh, Dhananjay; Babar, Mustafeez Mujtaba; Inayathullah, Mohammed; Solow-Cordero, David E.; Kim, Kwangmin; Samineni, Aneesh V.; Parekh, Mansi; Tayebi, Lobat; Rajadas, Jayakumar

doi:10.2147/dddt.s101486

Cited by 53 publications

(49 citation statements)

References 59 publications

(74 reference statements)

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“…The clinical trial document refers to three previous articles (22,26,27). In 2016, Pothineni et al published an in vitro high-throughput screening of more than 4,300 drug candidates, against Borrelia burgdorferi grown to its stationary-phase (26). DSF appeared to be a very efficient bactericidal molecule for Borrelia in vitro, but no in vivo results have been reported yet.…”

Section: A Clinical Trial With Dsf For Treating Lyme Diseasementioning

confidence: 99%

Potential Patient-Reported Toxicities With Disulfiram Treatment in Late Disseminated Lyme Disease

Trautmann

Gascan

Ghozzi³

2020

Front. Med.

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Recently, disulfiram has been proposed as a promising treatment for people suffering from persistent symptoms of Lyme Disease. Disulfiram has several distinct molecular targets. The most well-known is alcohol dehydrogenase, a key enzyme for detoxifying the organism after alcohol ingestion. Other targets and modes of action of disulfiram, that may present problematic side effects, are less commonly mentioned. The French Federation against Tick Borne Diseases (French acronym, FFMVT), which associates three main Lyme patient organizations, MDs and PhDs, has recently been alerted to severe and persistent toxic events in a patient suffering from a late disseminated form of Lyme Disease following disulfiram intake. FFMVT reacted by launching a national call to examine whether other patients in France following a similar treatment could be identified, and what benefits, or side effects could be reported. The statements of 16 patients taking disulfiram have been collected and are presented here. Thirteen out of 16 patients reported toxic events, and seven out of 16 reported benefits for at least part of their symptoms. Based on the collected observations, it seems too early to promote disulfiram as a promising new treatment until the reasons underlying the reported toxicities have been explored, and the results of a well-conducted double blind clinical trial published. The importance of taking into account patient-reported outcomes in Lyme Disease is underlined by the present study.

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Section: A Clinical Trial With Dsf For Treating Lyme Diseasementioning

confidence: 99%

Potential Patient-Reported Toxicities With Disulfiram Treatment in Late Disseminated Lyme Disease

Trautmann

Gascan

Ghozzi³

2020

Front. Med.

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“…A fluorescence-based assay that uses a two-dye combination to monitor cellular intactness, and thereby viability, has been optimized for Bb [244]. Another group has optimized a luciferase-based assay to measure ATP levels to monitor viability as a function of energy metabolism [245]. It is hoped that as other groups use these assays, a consensus protocol will be achieved, allowing for the direct comparison of reported antibiotic sensitivities of Bb.…”

Section: Laboratory Determination Of Antibiotic Susceptibilitiesmentioning

confidence: 99%

“…Several, more 'natural', compounds have been tested, including essential oils [300], phytochemicals [301] and bee venom [302]; however, the financial input required to take these compounds to clinical trials makes it unlikely that these treatments will get the rigorous testing they would require to be clinically accepted. A number of studies have screened FDA-approved drugs for their potential as novel Bb antibiotic candidates [245,273], and have identified antibiotics previously untested on Bb that showed good efficacy. Studying drugs that are already FDA-approved bypasses the requirement for the early stages of clinical trials, and reduces the financial burden in bringing new Bb treatments to the clinic.…”

Section: Alternative Anti-microbial Treatmentsmentioning

confidence: 99%

Lyme Disease Frontiers: Reconciling Borrelia Biology and Clinical Conundrums

Bamm

Mainprize

et al. 2019

Pathogens

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Lyme disease is a complex tick-borne zoonosis that poses an escalating public health threat in several parts of the world, despite sophisticated healthcare infrastructure and decades of effort to address the problem. Concepts like the true burden of the illness, from incidence rates to longstanding consequences of infection, and optimal case management, also remain shrouded in controversy. At the heart of this multidisciplinary issue are the causative spirochetal pathogens belonging to the Borrelia Lyme complex. Their unusual physiology and versatile lifestyle have challenged microbiologists, and may also hold the key to unlocking mysteries of the disease. The goal of this review is therefore to integrate established and emerging concepts of Borrelia biology and pathogenesis, and position them in the broader context of biomedical research and clinical practice. We begin by considering the conventions around diagnosing and characterizing Lyme disease that have served as a conceptual framework for the discipline. We then explore virulence from the perspective of both host (genetic and environmental predispositions) and pathogen (serotypes, dissemination, and immune modulation), as well as considering antimicrobial strategies (lab methodology, resistance, persistence, and clinical application), and borrelial adaptations of hypothesized medical significance (phenotypic plasticity or pleomorphy).

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“…Taking in to consideration of the limiting effects of standard antibiotics and our search to identify safe and effective molecules to kill the persisters of B. burgdorferi, we screened 7450 chemical compounds (80% FDA approved) from several different libraries, using a BacTiter-Glo ™ Assay. We have identified nearly 300 hit molecules and evaluated the top 50 hit molecules by in vitro efficacy stuides 8,26 . The molecules azlocillin and cefotaxime were chosen for the current study based on their safety and ability to kill Borrelia at low concentrations in in vitro 8,27 .…”

mentioning

confidence: 99%

“…We have identified nearly 300 hit molecules and evaluated the top 50 hit molecules by in vitro efficacy stuides 8,26 . The molecules azlocillin and cefotaxime were chosen for the current study based on their safety and ability to kill Borrelia at low concentrations in in vitro 8,27 . Our aim was to repurpose the identified FDA approved drugs for the use of Lyme disease treatment.…”

mentioning

confidence: 99%

Azlocillin can be the potential drug candidate against drug-tolerant Borrelia burgdorferi sensu stricto JLB31

Pothineni

Potula

Ambati

et al. 2020

Sci Rep

Self Cite

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Lyme disease is one of most common vector-borne diseases, reporting more than 300,000 cases annually in the United States. treating Lyme disease during its initial stages with traditional tetracycline antibiotics is effective. However, 10-20% of patients treated with antibiotic therapy still shows prolonged symptoms of fatigue, musculoskeletal pain, and perceived cognitive impairment. When these symptoms persists for more than 6 months to years after completing conventional antibiotics treatment are called post-treatment Lyme disease syndrome (ptLDS). though the exact reason for the prolongation of post treatment symptoms are not known, the growing evidence from recent studies suggests it might be due to the existence of drug-tolerant persisters. In order to identify effective drug molecules that kill drug-tolerant borrelia we have tested two antibiotics, azlocillin and cefotaxime that were identified by us earlier. The in vitro efficacy studies of azlocillin and cefotaxime on drug-tolerant persisters were done by semisolid plating method. the results obtained were compared with one of the currently prescribed antibiotic doxycycline. We found that azlocillin completely kills late log phase and 7-10 days old stationary phase B. burgdorferi. our results also demonstrate that azlocillin and cefotaxime can effectively kill in vitro doxycycline-tolerant B. burgdorferi. Moreover, the combination drug treatment of azlocillin and cefotaxime effectively killed doxycycline-tolerant B. burgdorferi. furthermore, when tested in vivo, azlocillin has shown good efficacy against B. burgdorferi in mice model. These seminal findings strongly suggests that azlocillin can be effective in treating B. burgdorferi sensu stricto JLB31 infection and furthermore in depth research is necessary to evaluate its potential use for Lyme disease therapy. Lyme disease is a major vector-borne disease in the United States caused by Borrelia burgdorferi sensu lato which affects more than 300,000 people annually 1-3. Lyme disease affects various organs such as brain, skin, heart, joints, and nervous systems 4-6. The symptoms of Lyme disease are erythema migrans, fatigue, fever, headache, chills, muscle and joint pain 7,8. Current antibiotic treatment for Lyme disease is effective during early stages of disease and cures the infection in most patients 9. However, 10-20% of patients undergone antibiotic treatment still experience symptoms like pain, fatigue, arthralgia, and cognitive problems. If these symptoms prolong more than 6 months after treatment, it is referred to as Post-treatment Lyme Disease Syndrome (PTLDS) 9-12. Though the exact root cause for PTLDS is not known, research evidences suggests it might be presence of persister forms of B. burgdorferi or due to impaired immunological response 10,13,14. Many research studies has shown that B.

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Identification of new drug candidates against Borrelia burgdorferi using high-throughput screening

Cited by 53 publications

References 59 publications

Potential Patient-Reported Toxicities With Disulfiram Treatment in Late Disseminated Lyme Disease

Potential Patient-Reported Toxicities With Disulfiram Treatment in Late Disseminated Lyme Disease

Lyme Disease Frontiers: Reconciling Borrelia Biology and Clinical Conundrums

Azlocillin can be the potential drug candidate against drug-tolerant Borrelia burgdorferi sensu stricto JLB31

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