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Identification of novel activity against Borrelia burgdorferi persisters using an FDA approved drug library.

ABSTRACT: Although antibiotic treatment for Lyme disease is effective in the majority of cases, especially during the early phase of the disease, a minority of patients suffer from post-treatment Lyme disease syndrome (PTLDS). It is unclear what mechanisms drive this problem, and although slow or ineffective killing of Borrelia burgdorferi has been suggested as an explanation, there is a lack of evidence that viable organisms are present in PTLDS. Although not a clinical surrogate, insight may be gained by examining stationary-phase in vitro Borrelia burgdorferi persisters that survive treatment with the antibiotics doxycycline and amoxicillin. To identify drug candidates that can eliminate B. burgdorferi persisters more effectively, we screened an Food and Drug Administration (FDA)-approved drug library consisting of 1524 compounds against stationary-phase B. burgdorferi by using a newly developed high throughput SYBR Green I/propidium iodide (PI) assay. We identified 165 agents approved for use in other disease conditions that had more activity than doxycycline and amoxicillin against B. burgdorferi persisters. The top 27 drug candidates from the 165 hits were confirmed to have higher anti-persister activity than the current frontline antibiotics. Among the top 27 confirmed drug candidates from the 165 hits, daptomycin, clofazimine, carbomycin, sulfa drugs (e.g., sulfamethoxazole), and certain cephalosporins (e.g. cefoperazone) had the highest anti-persister activity. In addition, some drug candidates, such as daptomycin and clofazimine (which had the highest activity against non-growing persisters), had relatively poor activity or a high minimal inhibitory concentration (MIC) against growing B. burgdorferi. Our findings may have implications for the development of a more effective treatment for Lyme disease and for the relief of long-term symptoms that afflict some Lyme disease patients.

SUBMITTER: Feng J

PROVIDER: S-EPMC4126181 | biostudies-other | 2014 Jul

REPOSITORIES: biostudies-other

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Project description:Lyme disease is a leading vector-borne disease in the United States. Although the majority of Lyme patients can be cured with standard 2-4 week antibiotic treatment, 10%-20% of patients continue to suffer from prolonged post-treatment Lyme disease syndrome (PTLDS). While the cause for this is unclear, persisting organisms not killed by current Lyme antibiotics may be involved. In our previous study, we screened an FDA drug library and reported 27 top hits that showed high activity against Borrelia persisters. In this study, we present the results of an additional 113 active hits that have higher activity against the stationary phase B. burgdorferi than the currently used Lyme antibiotics. Many antimicrobial agents (antibiotics, antivirals, antifungals, anthelmintics or antiparasitics) used for treating other infections were found to have better activity than the current Lyme antibiotics. These include antibacterials such as rifamycins (3-formal-rifamycin, rifaximin, rifamycin SV), thiostrepton, quinolone drugs (sarafloxacin, clinafloxacin, tosufloxacin), and cell wall inhibitors carbenicillin, tazobactam, aztreonam; antifungal agents such as fluconazole, mepartricin, bifonazole, climbazole, oxiconazole, nystatin; antiviral agents zanamivir, nevirapine, tilorone; antimalarial agents artemisinin, methylene blue, and quidaldine blue; antihelmintic and antiparasitic agents toltrazuril, tartar emetic, potassium antimonyl tartrate trihydrate, oxantel, closantel, hycanthone, pyrimethamine, and tetramisole. Interestingly, drugs used for treating other non-infectious conditions including verteporfin, oltipraz, pyroglutamic acid, pidolic acid, and dextrorphan tartrate, that act on the glutathione/?-glutamyl pathway involved in protection against free radical damage, and also the antidepressant drug indatraline, were found to have high activity against stationary phase B. burgdorferi. Among the active hits, agents that affect cell membranes, energy production, and reactive oxygen species production are more active against the B. burgdorferi persisters than the commonly used antibiotics that inhibit macromolecule biosynthesis. Future studies are needed to evaluate and optimize the promising active hits in drug combination studies in vitro and also in vivo in animal models. These studies may have implications for developing more effective treatments of Lyme disease.

Project description:Lassa virus (LASV) belongs to the Mammarenavirus genus (family Arenaviridae) and causes severe hemorrhagic fever in humans. At present, there are no Food and Drug Administration (FDA)-approved drugs or vaccines specific for LASV. Here, high-throughput screening of an FDA-approved drug library was performed against LASV entry by using pseudotype virus bearing LASV envelope glycoprotein (GPC). Two hit compounds, lacidipine and phenothrin, were identified as LASV entry inhibitors in the micromolar range. A mechanistic study revealed that both compounds inhibited LASV entry by blocking low-pH-induced membrane fusion. Accordingly, lacidipine showed virucidal effects on the pseudotype virus of LASV. Adaptive mutant analyses demonstrated that replacement of T40, located in the ectodomain of the stable-signal peptide (SSP), with lysine (K) conferred LASV resistance to lacidipine. Furthermore, lacidipine showed antiviral activity against LASV, the closely related Mopeia virus (MOPV), and the New World arenavirus Guanarito virus (GTOV). Drug-resistant variants indicated that V36M in the ectodomain of the SSP mutant and V436A in the transmembrane domain of the GP2 mutant conferred GTOV resistance to lacidipine, suggesting the interface between SSP and GP2 is the target of lacidipine. This study shows that lacidipine is a candidate for LASV therapy, reinforcing the notion that the SSP-GP2 interface provides an entry-targeted platform for arenavirus inhibitor design.IMPORTANCE Currently, there is no approved therapy to treat Lassa fever; therefore, repurposing of approved drugs will accelerate the development of a therapeutic stratagem. In this study, we screened an FDA-approved library of drugs and identified two compounds, lacidipine and phenothrin, which inhibited Lassa virus entry by blocking low-pH-induced membrane fusion. Additionally, both compounds extended their inhibition against the entry of Guanarito virus, and the viral targets were identified as the SSP-GP2 interface.

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Identification of novel activity against Borrelia burgdorferi persisters using an FDA approved drug library.

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