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Efficacy of two novel 2,2'-bifurans to inhibit methicillin-resistant Staphylococcus aureus infection in male mice in comparison to vancomycin.

El-Sayed WM, Hussin WA, Ismail MA - Drug Des Devel Ther (2012)

Bottom Line: Treatment with bifurans did not cause any toxicity.Treatment of MRSA-infected animals with bifurans resulted in significant reductions in the viable bacterial count in blood, liver, kidney, and spleen.Similar to vancomycin, bifurans ameliorated most of the previous effects.

View Article: PubMed Central - PubMed

Affiliation: Departments of Biological Sciences and Chemistry, King Faisal University, Al-Hofuf, Saudi Arabia. waelelhalawany@hotmail.com

ABSTRACT
The therapeutic efficacy of two novel bifurans and vancomycin in an animal model of a methicillin-resistant Staphylococcus aureus (MRSA) infection was compared. Adult male CF-1 mice (25-35 g) were intraperitoneally injected with 200 μL/mouse containing 10(7) cell-forming units of MRSA. After 16 hours, animals were treated with 110 mg/kg of vancomycin, or 5 mg/kg of mononitrile bifuran (1A) or monocationic bifuran (1B) and killed after 8 hours. Treatment with bifurans did not cause any toxicity. Treatment of MRSA-infected animals with bifurans resulted in significant reductions in the viable bacterial count in blood, liver, kidney, and spleen. Colonies recovered from livers and kidneys of mice injected with 1A or 1B lost the initial resistance pattern and became susceptible to methicillin and ciprofloxacin. MRSA elevated the serum urea level and activities of alanine aminotransferase and γ-glutamyl transpeptidase. MRSA also elevated the hepatic level of malondialdehyde, and serum levels of tumor necrosis factor and interleukin-6. MRSA also reduced the glutathione content and activities of catalase and glutathione S-transferase in liver. Similar to vancomycin, bifurans ameliorated most of the previous effects. Compound 1B was superior to 1A, and sometimes both provided better antistaphylococcal agents than vancomycin against MRSA pathogenesis. The present findings along with our previous studies support further evaluation of the efficacy of these bifurans in clinical studies.

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Viable bacterial count (log10 CFU/mL blood or g tissue) in blood (A), liver (B), kidney (C), and spleen (D).Notes: Data are expressed as means ± standard error of mean, n = 5. aSignificant difference (P < 0.05) compared to untreated infected group.
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f2-dddt-6-279: Viable bacterial count (log10 CFU/mL blood or g tissue) in blood (A), liver (B), kidney (C), and spleen (D).Notes: Data are expressed as means ± standard error of mean, n = 5. aSignificant difference (P < 0.05) compared to untreated infected group.

Mentions: On challenging mice with intraperitoneal injection of MRSA that was also resistant to ciprofloxacin and ampicillin, all animals developed bacteremia 24 hours postchallenge. The LD50 of bifurans investigated was 50 mg/kg, at which 20 out of 40 mice developed severe toxicity and died within 24 hours. The injection of a single dose of these bifurans at 5 mg/kg resulted in a 100% survival rate in mice, and no toxicity signs appeared for 4 weeks postinjection. Intraperitoneal treatment of infected animals with a single dose of either vancomycin at 110 mg/kg or bifurans (1A or 1B) at 5 mg/kg for 8 hours resulted in significant reductions in the viable bacterial count in blood (Figure 2A). Bifurans were as efficacious as vancomycin in reducing the bacterial count (log10 CFU) significantly in liver (Figure 2B), kidney (Figure 2C), and spleen (Figure 2D) as compared to infected untreated animals. The number of colonies recovered from these organs was higher than that recovered from blood, but the reduction percentage from control was almost the same. The morphology and microscopic examination of all colonies were identical to those of the inoculation strain. Selected colonies recovered from all organs of mice injected with vancomycin were allowed to grow overnight and showed the same resistance pattern as the strain used for injection of mice (Table 1). On the other hand, colonies recovered from livers and kidneys of mice injected with either bifuran investigated lost the initial resistance pattern and became susceptible to ampicillin, methicillin, or ciprofloxacin at 4 μg/mL and remained so after three passages (Table 1). However, colonies recovered from spleens of mice injected with 1A did not lose the initial resistance pattern, while those isolated from spleens of mice treated with 1B lost the initial resistance profile (Table 1).


Efficacy of two novel 2,2'-bifurans to inhibit methicillin-resistant Staphylococcus aureus infection in male mice in comparison to vancomycin.

El-Sayed WM, Hussin WA, Ismail MA - Drug Des Devel Ther (2012)

Viable bacterial count (log10 CFU/mL blood or g tissue) in blood (A), liver (B), kidney (C), and spleen (D).Notes: Data are expressed as means ± standard error of mean, n = 5. aSignificant difference (P < 0.05) compared to untreated infected group.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3472655&req=5

f2-dddt-6-279: Viable bacterial count (log10 CFU/mL blood or g tissue) in blood (A), liver (B), kidney (C), and spleen (D).Notes: Data are expressed as means ± standard error of mean, n = 5. aSignificant difference (P < 0.05) compared to untreated infected group.
Mentions: On challenging mice with intraperitoneal injection of MRSA that was also resistant to ciprofloxacin and ampicillin, all animals developed bacteremia 24 hours postchallenge. The LD50 of bifurans investigated was 50 mg/kg, at which 20 out of 40 mice developed severe toxicity and died within 24 hours. The injection of a single dose of these bifurans at 5 mg/kg resulted in a 100% survival rate in mice, and no toxicity signs appeared for 4 weeks postinjection. Intraperitoneal treatment of infected animals with a single dose of either vancomycin at 110 mg/kg or bifurans (1A or 1B) at 5 mg/kg for 8 hours resulted in significant reductions in the viable bacterial count in blood (Figure 2A). Bifurans were as efficacious as vancomycin in reducing the bacterial count (log10 CFU) significantly in liver (Figure 2B), kidney (Figure 2C), and spleen (Figure 2D) as compared to infected untreated animals. The number of colonies recovered from these organs was higher than that recovered from blood, but the reduction percentage from control was almost the same. The morphology and microscopic examination of all colonies were identical to those of the inoculation strain. Selected colonies recovered from all organs of mice injected with vancomycin were allowed to grow overnight and showed the same resistance pattern as the strain used for injection of mice (Table 1). On the other hand, colonies recovered from livers and kidneys of mice injected with either bifuran investigated lost the initial resistance pattern and became susceptible to ampicillin, methicillin, or ciprofloxacin at 4 μg/mL and remained so after three passages (Table 1). However, colonies recovered from spleens of mice injected with 1A did not lose the initial resistance pattern, while those isolated from spleens of mice treated with 1B lost the initial resistance profile (Table 1).

Bottom Line: Treatment with bifurans did not cause any toxicity.Treatment of MRSA-infected animals with bifurans resulted in significant reductions in the viable bacterial count in blood, liver, kidney, and spleen.Similar to vancomycin, bifurans ameliorated most of the previous effects.

View Article: PubMed Central - PubMed

Affiliation: Departments of Biological Sciences and Chemistry, King Faisal University, Al-Hofuf, Saudi Arabia. waelelhalawany@hotmail.com

ABSTRACT
The therapeutic efficacy of two novel bifurans and vancomycin in an animal model of a methicillin-resistant Staphylococcus aureus (MRSA) infection was compared. Adult male CF-1 mice (25-35 g) were intraperitoneally injected with 200 μL/mouse containing 10(7) cell-forming units of MRSA. After 16 hours, animals were treated with 110 mg/kg of vancomycin, or 5 mg/kg of mononitrile bifuran (1A) or monocationic bifuran (1B) and killed after 8 hours. Treatment with bifurans did not cause any toxicity. Treatment of MRSA-infected animals with bifurans resulted in significant reductions in the viable bacterial count in blood, liver, kidney, and spleen. Colonies recovered from livers and kidneys of mice injected with 1A or 1B lost the initial resistance pattern and became susceptible to methicillin and ciprofloxacin. MRSA elevated the serum urea level and activities of alanine aminotransferase and γ-glutamyl transpeptidase. MRSA also elevated the hepatic level of malondialdehyde, and serum levels of tumor necrosis factor and interleukin-6. MRSA also reduced the glutathione content and activities of catalase and glutathione S-transferase in liver. Similar to vancomycin, bifurans ameliorated most of the previous effects. Compound 1B was superior to 1A, and sometimes both provided better antistaphylococcal agents than vancomycin against MRSA pathogenesis. The present findings along with our previous studies support further evaluation of the efficacy of these bifurans in clinical studies.

Show MeSH
Related in: MedlinePlus