Anthracimycin activity against contemporary methicillin-resistant Staphylococcus aureus

被引:0
作者
Mary E Hensler
Kyoung Hwa Jang
Wdee Thienphrapa
Lisa Vuong
Dan N Tran
Evaristus Soubih
Leo Lin
Nina M Haste
Mark L Cunningham
Bryan P Kwan
Karen Joy Shaw
William Fenical
Victor Nizet
机构
[1] University of California San Diego,Department of Pediatrics
[2] Center for Marine Biotechnology and Biomedicine,undefined
[3] Scripps Institution of Oceanography,undefined
[4] University of California San Diego,undefined
[5] Skaggs School of Pharmacy and Pharmaceutical Sciences,undefined
[6] University of California San Diego,undefined
[7] Trius Therapeutics,undefined
来源
The Journal of Antibiotics | 2014年 / 67卷
关键词
anthracimycin; methicillin-resistant; novel antibiotic;
D O I
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中图分类号
学科分类号
摘要
Anthracimycin is a recently discovered novel marine-derived compound with activity against Bacillus anthracis. We tested anthracimycin against an expanded panel of Staphylococcus aureus strains in vitro and in vivo. All strains of S. aureus tested, including methicillin-susceptible, methicillin-resistant (MRSA) and vancomycin-resistant strains of S. aureus, were susceptible to anthracimycin at MIC values of ⩽0.25 mg l−1. Although its postantibiotic effects were minimal, anthracimycin exhibited potent and rapid bactericidal activity, with a >4-log kill of USA300 MRSA within 3 h at five times its MIC. At concentrations significantly below the MIC, anthracimycin slowed MRSA growth and potentiated the bactericidal activity of the human cathelicidin, LL-37. The bactericidal activity of anthracimycin was somewhat mitigated in the presence of 20% human serum, and the compound was minimally toxic to human cells, with an IC50 (inhibitory concentration 50)=70 mg l−1 against human carcinoma cells. At concentrations near the MIC, anthracimycin inhibited S. aureus nucleic acid synthesis as determined by optimized macromolecular synthesis methodology, with inhibition of DNA and RNA synthesis occurring in the absence of DNA intercalation. Anthracimycin at a single dose of 1 or 10 mg kg−1 was able to protect mice from MRSA-induced mortality in a murine peritonitis model of infection. Anthracimycin provides an interesting new scaffold for future development of a novel MRSA antibiotic.
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页码:549 / 553
页数:4
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