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

Feng J, Wang T, Shi W, Zhang S, Sullivan D, Auwaerter PG, Zhang Y - Emerg Microbes Infect (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University , Baltimore, MD 21205, USA.

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.

No MeSH data available.


Related in: MedlinePlus

Representative images of stationary-phase B. burgdorferi strain B31 treated with different antibiotics (50 µM) followed by staining in the SYBR Green I/PI assay (×400 magnification). (A) Drug-free control, (B) Doxycycline, (C) Amoxicillin, (D) Daptomycin, (E) Cefoperazone, (F) Clofazimine, (G) Carbomycin, (H) Cefotiam, and (I) Tetracycline.
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fig3: Representative images of stationary-phase B. burgdorferi strain B31 treated with different antibiotics (50 µM) followed by staining in the SYBR Green I/PI assay (×400 magnification). (A) Drug-free control, (B) Doxycycline, (C) Amoxicillin, (D) Daptomycin, (E) Cefoperazone, (F) Clofazimine, (G) Carbomycin, (H) Cefotiam, and (I) Tetracycline.

Mentions: Antibiotics that have good activity against growing bacteria (a low MIC) may not have good activity against non-replicating persisters, and vice versa.30 However, some antibiotics, such as the new tuberculosis drug candidates TMC207 and PA-824, have good activity for growing bacteria and non-growing persisters.31 Thus, we sought to determine the MICs of some antibiotics with good anti-persister activity against B. burgdorferi using the new SYBR Green I/PI assay and microscope counting. The results obtained by the two methods had good overall concordance. The MIC values (Table 2) of doxycycline, amoxicillin, vancomycin, and metronidazole were in agreement with previous studies,23,24 and these antibiotics had low activity against B. burgdorferi persisters. We also observed that the macrolide carbomycin, cephalosporins, cefoperazone and cefotiam, and sulfamethoxazole, were highly active against log-phase replicating B. burgdorferi, having low MICs (Table 2) in addition to having good activity for stationary-phase B. burgdorferi persisters. Conversely, daptomycin and clofazimine were less potent against replicating B. burgdorferi, having relatively high MICs, 12.5–25 µg/mL and 6.25 µg/mL, respectively, but had excellent anti-persister activity (Table 2, Figures 3D and 3G). With the exception of clofazimine and metronidazole, the Cmax values of the drug candidates were generally higher than the MIC values (Table 2).


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

Feng J, Wang T, Shi W, Zhang S, Sullivan D, Auwaerter PG, Zhang Y - Emerg Microbes Infect (2014)

Representative images of stationary-phase B. burgdorferi strain B31 treated with different antibiotics (50 µM) followed by staining in the SYBR Green I/PI assay (×400 magnification). (A) Drug-free control, (B) Doxycycline, (C) Amoxicillin, (D) Daptomycin, (E) Cefoperazone, (F) Clofazimine, (G) Carbomycin, (H) Cefotiam, and (I) Tetracycline.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4126181&req=5

fig3: Representative images of stationary-phase B. burgdorferi strain B31 treated with different antibiotics (50 µM) followed by staining in the SYBR Green I/PI assay (×400 magnification). (A) Drug-free control, (B) Doxycycline, (C) Amoxicillin, (D) Daptomycin, (E) Cefoperazone, (F) Clofazimine, (G) Carbomycin, (H) Cefotiam, and (I) Tetracycline.
Mentions: Antibiotics that have good activity against growing bacteria (a low MIC) may not have good activity against non-replicating persisters, and vice versa.30 However, some antibiotics, such as the new tuberculosis drug candidates TMC207 and PA-824, have good activity for growing bacteria and non-growing persisters.31 Thus, we sought to determine the MICs of some antibiotics with good anti-persister activity against B. burgdorferi using the new SYBR Green I/PI assay and microscope counting. The results obtained by the two methods had good overall concordance. The MIC values (Table 2) of doxycycline, amoxicillin, vancomycin, and metronidazole were in agreement with previous studies,23,24 and these antibiotics had low activity against B. burgdorferi persisters. We also observed that the macrolide carbomycin, cephalosporins, cefoperazone and cefotiam, and sulfamethoxazole, were highly active against log-phase replicating B. burgdorferi, having low MICs (Table 2) in addition to having good activity for stationary-phase B. burgdorferi persisters. Conversely, daptomycin and clofazimine were less potent against replicating B. burgdorferi, having relatively high MICs, 12.5–25 µg/mL and 6.25 µg/mL, respectively, but had excellent anti-persister activity (Table 2, Figures 3D and 3G). With the exception of clofazimine and metronidazole, the Cmax values of the drug candidates were generally higher than the MIC values (Table 2).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University , Baltimore, MD 21205, USA.

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.

No MeSH data available.


Related in: MedlinePlus