TarO-specific inhibitors of wall teichoic acid biosynthesis restore β-lactam efficacy against methicillin-resistant staphylococci

被引：94

作者：

Lee, Sang Ho ^{[1
]}

Wang, Hao ^{[1
]}

Labroli, Marc ^{[2
]}

Koseoglu, Sandra ^{[1
]}

Zuck, Paul ^{[2
]}

Mayhood, Todd ^{[1
]}

Gill, Charles ^{[1
]}

Mann, Paul ^{[1
]}

Sher, Xinwei ^{[3
]}

Ha, Sookhee ^{[1
]}

Yang, Shu-Wei ^{[1
]}

Mandal, Mihir ^{[1
]}

Yang, Christine ^{[1
]}

Liang, Lianzhu ^{[1
]}

Tan, Zheng ^{[1
]}

Tawa, Paul ^{[1
]}

Hou, Yan ^{[1
]}

Kuvelkar, Reshma ^{[1
]}

DeVito, Kristine ^{[1
]}

Wen, Xiujuan ^{[1
]}

Xiao, Jing ^{[1
]}

Batchlett, Michelle ^{[2
]}

Balibar, Carl J. ^{[1
]}

Liu, Jenny ^{[1
]}

Xiao, Jianying ^{[1
]}

Murgolo, Nicholas ^{[1
]}

Garlisi, Charles G. ^{[1
]}

Sheth, Payal R. ^{[1
]}

Flattery, Amy ^{[1
]}

Su, Jing ^{[1
]}

Tan, Christopher ^{[1
]}

Roemer, Terry ^{[1
]}

机构：

[1] Merck Res Labs, Kenilworth, NJ 07033 USA

[2] Merck Res Labs, West Point, PA 19486 USA

[3] Merck Res Labs, Boston, MA 02115 USA

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2016年 / 8卷 / 329期

关键词：

CELL-WALL; BACILLUS-SUBTILIS; AUREUS; ANTIBIOTICS; GENE; MRSA; GLYCOSYLATION; COMBINATIONS; TRANSFERASE; TUNICAMYCIN;

D O I：

10.1126/scitranslmed.aad7364

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The widespread emergence of methicillin-resistant Staphylococcus aureus (MRSA) has dramatically eroded the efficacy of current beta-lactam antibiotics and created an urgent need for new treatment options. We report an S. aureus phenotypic screening strategy involving chemical suppression of the growth inhibitory consequences of depleting latest age wall teichoic acid biosynthesis. This enabled us to identify early-stage pathway-specific inhibitors of wall teichoic acid biosynthesis predicted to be chemically synergistic with beta-lactams. We demonstrated by genetic and biochemical means that each of the new chemical series discovered, herein named tarocin A and tarocin B, inhibited the first step in wall teichoic acid biosynthesis (TarO). Tarocins do not have intrinsic bioactivity but rather demonstrated potent bactericidal synergy in combination with broad-spectrum beta-lactam antibiotics against diverse clinical isolates of methicillin-resistant staphylococci as well as robust efficacy in a murine infection model of MRSA. Tarocins and other inhibitors of wall teichoic acid biosynthesis may provide a rational strategy to develop Gram-positive bactericidal b-lactam combination agents active against methicillin-resistant staphylococci.

引用

页数：14

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