Azalomycin F<sub>5a</sub>, a 36-membered macrocyclic lactone isolated from several streptomyces strains, presented remarkable anti-methicillin-resistant Staphylococcus aureus (MRSA) activities. To improve ...Azalomycin F<sub>5a</sub>, a 36-membered macrocyclic lactone isolated from several streptomyces strains, presented remarkable anti-methicillin-resistant Staphylococcus aureus (MRSA) activities. To improve its anti-MRSA potential and to evaluate the probability of MRSA resistant to it before development, the anti-MRSA activities of azalomycin F<sub>5a</sub> in combination with vitamin K<sub>3</sub> were first evaluated using checkerboard assay. Then the minimal concentration inhibiting colony formation by 99% (MIC<sub>99</sub>) and mutant prevention concentration (MPC) of azalomycin F<sub>5a</sub> alone and in combination with vitamin K<sub>3</sub> against MRSA were determined using agar plates with linear antimicrobial concentration decrease. The fractional inhibitory concentration indexes (FICIs) of 0.25 - 0.50 showed the synergistic activity of azalomycin F<sub>5a</sub> in combination with vitamin K<sub>3</sub>. The mutant selection windows (MSWs, MIC<sub>99</sub>-MPC) of azalomycin F<sub>5a</sub> alone against MRSA tested were 2.07 - 6.40 μg/mL, and the MPCs of azalomycin F<sub>5a</sub> in combination with vitamin K<sub>3</sub> against MRSA tested were 1.60 - 3.20 μg/mL. These indicated that the MPCs of azalomycin F<sub>5a</sub> in combination could drop down to below its MIC<sub>99</sub> alone. According to the hypothesis of MSW, the narrower MSWs of azalomycin F<sub>5a </sub>alone, even closed MSWs in combination with vitamin K<sub>3</sub>, together with their synergistic anti-MRSA activities, indicated that azalomycin F<sub>5a </sub>had a good potential to develop as a new antimicrobial agent.展开更多
AIM: To discover anti-methicillin-resistant Staphylococcus aureus(anti-MRSA) microbial natural products or their derivatives. METHOD: Azalomycin F5a(1) was prepared through fermentation of Streptomyces hygroscopicus v...AIM: To discover anti-methicillin-resistant Staphylococcus aureus(anti-MRSA) microbial natural products or their derivatives. METHOD: Azalomycin F5a(1) was prepared through fermentation of Streptomyces hygroscopicus var. azalomyceticus, and its derivatives were synthesized through hydrocarbylation in hydrocarbyl alcoholic-AcOH(4 : 1) and subsequent demalonylation with 2 mol·L-1 KOH in MeOH-H2O(7 : 3). Their activities against MRSA ATCC 33592 and three clinical MRSA isolates were evaluated by the agar diffusion and broth microdilution methods. RESULTS: Four demalonylazalomycin F5a derivatives 2 to 5 were synthesized. The anti-MRSA activity assay indicated that compounds 1 to 5 showed remarkable activity against MRSA, and their minimum inhibitory concentrations(MICs) were respectively 3.0-4.0, 0.5-1.0, 0.67-1.0, 0.67-0.83, and 0.5-0.83 μg·mL-1. CONCLUSION: Azalomycin F5a and the demalonylazalomycin F5a derivatives 2-5 showed remarkable anti-MRSA activity, and the anti-MRSA activities of 2 to 5 were higher than that of 1, while the anti-MRSA activities of 2 to 5 showed no obvious differences. It was also shown that the malonyl monoester group of azalomycin F5a was less important for its anti-MRSA activity.展开更多
文摘Azalomycin F<sub>5a</sub>, a 36-membered macrocyclic lactone isolated from several streptomyces strains, presented remarkable anti-methicillin-resistant Staphylococcus aureus (MRSA) activities. To improve its anti-MRSA potential and to evaluate the probability of MRSA resistant to it before development, the anti-MRSA activities of azalomycin F<sub>5a</sub> in combination with vitamin K<sub>3</sub> were first evaluated using checkerboard assay. Then the minimal concentration inhibiting colony formation by 99% (MIC<sub>99</sub>) and mutant prevention concentration (MPC) of azalomycin F<sub>5a</sub> alone and in combination with vitamin K<sub>3</sub> against MRSA were determined using agar plates with linear antimicrobial concentration decrease. The fractional inhibitory concentration indexes (FICIs) of 0.25 - 0.50 showed the synergistic activity of azalomycin F<sub>5a</sub> in combination with vitamin K<sub>3</sub>. The mutant selection windows (MSWs, MIC<sub>99</sub>-MPC) of azalomycin F<sub>5a</sub> alone against MRSA tested were 2.07 - 6.40 μg/mL, and the MPCs of azalomycin F<sub>5a</sub> in combination with vitamin K<sub>3</sub> against MRSA tested were 1.60 - 3.20 μg/mL. These indicated that the MPCs of azalomycin F<sub>5a</sub> in combination could drop down to below its MIC<sub>99</sub> alone. According to the hypothesis of MSW, the narrower MSWs of azalomycin F<sub>5a </sub>alone, even closed MSWs in combination with vitamin K<sub>3</sub>, together with their synergistic anti-MRSA activities, indicated that azalomycin F<sub>5a </sub>had a good potential to develop as a new antimicrobial agent.
基金supported by the Jiangxi Province Science and Technology Supporting Plan(No.20111BBG7006-1)the National Natural Science Foundation of China(No.81260476)
文摘AIM: To discover anti-methicillin-resistant Staphylococcus aureus(anti-MRSA) microbial natural products or their derivatives. METHOD: Azalomycin F5a(1) was prepared through fermentation of Streptomyces hygroscopicus var. azalomyceticus, and its derivatives were synthesized through hydrocarbylation in hydrocarbyl alcoholic-AcOH(4 : 1) and subsequent demalonylation with 2 mol·L-1 KOH in MeOH-H2O(7 : 3). Their activities against MRSA ATCC 33592 and three clinical MRSA isolates were evaluated by the agar diffusion and broth microdilution methods. RESULTS: Four demalonylazalomycin F5a derivatives 2 to 5 were synthesized. The anti-MRSA activity assay indicated that compounds 1 to 5 showed remarkable activity against MRSA, and their minimum inhibitory concentrations(MICs) were respectively 3.0-4.0, 0.5-1.0, 0.67-1.0, 0.67-0.83, and 0.5-0.83 μg·mL-1. CONCLUSION: Azalomycin F5a and the demalonylazalomycin F5a derivatives 2-5 showed remarkable anti-MRSA activity, and the anti-MRSA activities of 2 to 5 were higher than that of 1, while the anti-MRSA activities of 2 to 5 showed no obvious differences. It was also shown that the malonyl monoester group of azalomycin F5a was less important for its anti-MRSA activity.
