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Sci Transl Med. 2016 Mar 9;8(329):329ra32. doi: 10.1126/scitranslmed.aad7364.

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

Author information

1
Merck Research Laboratories, Kenilworth, NJ 07033, USA.
2
Merck Research Laboratories, West Point, PA 19486, USA.
3
Merck Research Laboratories, Boston, MA 02115, USA.
4
Merck Research Laboratories, Kenilworth, NJ 07033, USA. jing.su2@merck.com christopher_tan@merck.com terry_roemer@merck.com.

Abstract

The widespread emergence of methicillin-resistant Staphylococcus aureus (MRSA) has dramatically eroded the efficacy of current β-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 late-stage 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 β-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 β-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 β-lactam combination agents active against methicillin-resistant staphylococci.

PMID:
26962156
DOI:
10.1126/scitranslmed.aad7364
[Indexed for MEDLINE]

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